sentence,pmcid,gene1,gene2,variant1,variant2,label
"On the other hand, @GENE$ overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of @GENE$ L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the @VARIANT$ mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f).",7067772,EphA2;20929,pendrin;20132,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be DFNB7/11, @GENE$, and DFNB16, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in @GENE$ (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (WFS1) (NM_001145853) according to TES.",4998745,DFNB3;56504,GJB2;2975,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"The two variants chr18:@VARIANT$ for @GENE$ and chr1:228462101 G>A for @GENE$ lead to novel missense variants, p.R222Q and @VARIANT$ respectively.",5611365,NFATC1;32336,OBSCN;70869,77170979 G>A;tmVar:g|SUB|G|77170979|A;HGVS:g.77170979G>A;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692,p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 3;7338,GJB6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes.     ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(@VARIANT$).",6567512,BBS7;12395,BBS6;10318,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"M1, @GENE$: p.(A179fs*18). M2, CYP1B1: p.(E387K). M3, CYP1B1: @VARIANT$. M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E173*);tmVar:p|SUB|E|173|*;HGVS:p.E173*;VariantGroup:11;CorrespondingGene:1545,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"Patient 3 was found to harbor a previously reported p.Arg84His variant in NR5A1, alongside a rare variant in @GENE$ (@VARIANT$, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). We also identified a monoallelic change in SRD5A2 (c.G680A, p.Arg227Gln, rs9332964:G>A) in Patient 11, who also harbored a @VARIANT$ of @GENE$ (Table 3).",5765430,ZFPM2;8008,NR5A1;3638,c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963,single codon deletion at position 372;tmVar:|Allele|SINGLECODON|CODON372;VariantGroup:21;CorrespondingGene:2516,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and CYP1B1 by co-transfection and pull-down assays in HEK293 cells.",5953556,CYP1B1;68035,TEK;397,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"Synergistic Mutations of @GENE$ and @GENE$ in Familial Tooth Agenesis Familial tooth agenesis (FTA), distinguished by developmental failure of selected teeth, is one of the most prevalent craniofacial anomalies in humans. Mutations in genes involved in WNT/beta-catenin signaling, including AXIN2 WNT10A, WNT10B, LRP6, and KREMEN1, are known to cause FTA. However, mutational interactions among these genes have not been fully explored. In this study, we characterized four FTA kindreds with LRP6 pathogenic mutations: p.(Gln1252*), p.(@VARIANT$), @VARIANT$, and p.(Asn1075Ser).",8621929,LRP6;1747,WNT10A;22525,Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,p.(Ala754Pro);tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Our study suggests that the @GENE$-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-@VARIANT$ heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Using SIFT and PolyPhen, the @VARIANT$ variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and @VARIANT$ (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, @GENE$ p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,ANG;74385,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
"(A) The @GENE$ mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and @GENE$ mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Our results indicate that the novel @GENE$-@VARIANT$ variant can be a pathogenic LQTS mutation, whereas @GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$ could be LQTS modifiers.",5578023,KCNH2;201,KCNQ1;85014,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"So, it is impossible to detect a mutation in a region which is not covered using this system (Case #9: @VARIANT$). Secondarily, the MPS system used in this study, is not effective for detecting homo-polymer regions, for example poly C stretch (Case #8: @VARIANT$). In addition, concerning pathogenecity of mutations identified, functional analysis will be necessary to draw the final conclusion in the future. In UK and US Caucasian USH1 patients, USH1B (@GENE$) has been reported as the most common USH1 genetic subtype, while @GENE$ (PCDH15) has been reported as the most common USH1 genetic subtype in North American Ashkenazi Jews.",3949687,MYO7A;219,USH1F;23401,c.5821-2A>G;tmVar:c|SUB|A|5821-2|G;HGVS:c.5821-2A>G;VariantGroup:42;CorrespondingGene:64072,p.Lys542GlnfsX5;tmVar:p|FS|K|542|Q|5;HGVS:p.K542QfsX5;VariantGroup:6;CorrespondingGene:4647;RS#:782077721;CA#:6197531,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,CYP1B1;68035,TEK;397,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"      Mutation detection in the family (a) Identification of the recurrent nonsense mutation @VARIANT$ in the @GENE$ gene. Note the heterozygous C T transition substitution at nucleotide position 3421 (arrow). (b, d) Identification of missense mutations @VARIANT$ and p.S300F in the @GENE$ gene.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with VAPB p.M170I and @GENE$ p.R408C with @GENE$ @VARIANT$ and SETX p.T14I).,4293318,TAF15;131088,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"  Human @GENE$ and @GENE$, were subcloned from human full-length cDNA (ADD3: clone IMAGE: 6649991; KAT2B clone IMAGE: 30333414) into the expression vectors pLentiGIII and PLEX-MCS, respectively. An HA tag was added in frame, before the stop codon, to the C terminus of ADD3 and KAT2B. The ADD3 @VARIANT$ and KAT2B @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol.",5973622,ADD3;40893,KAT2B;20834,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,0
"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes.     ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90.",3842385,EDA;1896,WNT10A;22525,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,0
"GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant @GENE$ proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 A115P and R368H showed perturbed interaction with HA-TEK. The residues E103, @VARIANT$, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d). This suggested that either the N-terminal TEK domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the TEK protein, which affected a secondary @GENE$-binding site.",5953556,TEK;397,CYP1B1;68035,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148;tmVar:p|Allele|I|148;VariantGroup:5;CorrespondingGene:7010;RS#:35969327,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for @GENE$ @VARIANT$. (b) Electropherograms of unaffected family member (II-2) and subject with BSP+ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of Arg37 among vertebrates                TOR2A missense variant A @GENE$ nonsynonymous SNV (@VARIANT$ [NM_130459.3], p.Arg190Cys [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,REEP4;11888,TOR2A;25260,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in @GENE$ were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the SLC20A2 mutation and secondarily from the PDGFRB variant. Currently, the genetic basis for the clinical heterogeneity of PFBC is not largely understood, and it cannot be explained only by a single variant. PFBC patients with biallelic variants in @GENE$ have been reported.",8172206,PDGFRB;1960,SLC20A2;68531,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK Q214P and @VARIANT$ alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,PAX3;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ @VARIANT$), 335F07 (@GENE$ @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR2;1078,FZD6;2617,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,0
   Two nucleotide variants in exon 8 (@VARIANT$; p.Glu290*) of the GCK gene and in exon 4 (@VARIANT$; p.Pro291Arg) of the HNF1A gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the @GENE$ variant was present in the father and the @GENE$ variant was present in the mother (Figure 1B).,8306687,GCK;55440,HNF1A;459,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,1
"This patient was subsequently found to carry a coexisting TIA1 variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. The authors raised the possibility of a digenic myopathy, which up to date has not been proven.     Herein, we describe the clinical and pathological phenotype of three unrelated probands harboring the combined heterozygous @GENE$ and @GENE$ variants in the setting of MRV or myofibrillar pathology, providing evidence that co-occurrence of these variants are associated with late-onset myopathy.",5868303,TIA1;20692,SQSTM1;31202,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"The genotypes of SLC20A2 (NM_001257180.2: @VARIANT$, p.His596Arg) and @GENE$ (NM_002609.4: c.317G>C, @VARIANT$) for available individuals are shown. Regarding @GENE$, A/G = heterozygous mutation carrier, and A/A = wild type; regarding PDGFRB, G/C = heterozygous mutation carrier, and G/G = wild type.",8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Proband 17 inherited CHD7 @VARIANT$ and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the @GENE$ @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,CDON;22996,FGFR1;69065,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a). The @VARIANT$ (p.His596Arg) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019).",8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB6;4936,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Five anencephaly cases carried rare or novel @GENE$ missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in @GENE$ and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD;8321;8323,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,0
"(D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.@VARIANT$, p.A2282T) vector plasmids and myc-tagged WT or mutant @GENE$ (@VARIANT$, p.R50C). Then, communoprecipitation assays were conducted. Western blot images are representative of n=3 experiments. AIS, adolescent idiopathic scoliosis; WT, wild type. To investigate the protein-protein interactions, we focused on AIS trios with multiple variants. We found that patients in two AIS trios (trios 22 and 27) carried variants in both the @GENE$ and TTC26 genes (figure 1).",7279190,TTC26;11786,FLNB;37480,R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260,0
"The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Mutations in NRXN1 and @GENE$ in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (c.2686C>T, @VARIANT$) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN2;86984,NRXN1;21005,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"Patient 3 was found to harbor a previously reported @VARIANT$ variant in @GENE$, alongside a rare variant in @GENE$ (c.A2107C, p.Met703Leu, @VARIANT$:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3).",5765430,NR5A1;3638,ZFPM2;8008,p.Arg84His;tmVar:p|SUB|R|84|H;HGVS:p.R84H;VariantGroup:0;CorrespondingGene:2516;RS#:543895681,rs121908603;tmVar:rs121908603;VariantGroup:3;CorrespondingGene:23414;RS#:121908603,1
"PKD1 sequencing identified a likely pathogenic variant, p.(@VARIANT$), absent in parents, and a second maternally inherited variant, p.(Ala561Val). This is extremely rare (never reported before, absent in GnomAD), but with benign computational predictions, and it was classified as hypomorphic. We cannot formally test if variants in these two patients are in trans, but we presume they contributed to the severe clinical expression. In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and @GENE$ (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in PKD2.",7224062,PKD1;250,PKD2;20104,Asn2167Asp;tmVar:p|SUB|N|2167|D;HGVS:p.N2167D;VariantGroup:33;CorrespondingGene:5310,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,0
Co-segregation of @GENE$ @VARIANT$ and @GENE$ @VARIANT$ was observed in two pedigrees and only a representative pedigree is shown.,5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1
"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the S100A3 protein (c.229C>T; @VARIANT$) and d) the @VARIANT$ (p.I80Gfs*13) in S100A13. Mutation name is based on the full-length @GENE$ (NM_002960) and @GENE$ (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"(A) In addition to c.235delC in @GENE$, the de novo variant of @GENE$, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3.",4998745,GJB2;2975,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Therefore, in this study, SCN5A @VARIANT$ may be the main cause of sinoatrial node dysfunction, whereas KCNH2 @VARIANT$ only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether @GENE$ mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. @GENE$ p.R1865H reduced the instability index of Nav1.5 protein and sodium current.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"@GENE$ Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, @VARIANT$ (c.100C>T) (rs121908073), and a novel variant, p.W482R of @GENE$ (TMC1) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,Transmembrane channel-like 1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R34X;tmVar:p|SUB|R|34|X;HGVS:p.R34X;VariantGroup:11;CorrespondingGene:117531;RS#:121908073;CA#:253002,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and @GENE$, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and @VARIANT$ exhibited diminished interaction with wild-type GFP-@GENE$. On the other hand, mutant GFP-CYP1B1 A115P and R368H showed perturbed interaction with HA-TEK.",5953556,TEK;397,CYP1B1;68035,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant p.(Lys205del). The @GENE$ gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,DUSP6;55621,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,0
"Interestingly, four of these @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while @GENE$ p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in @GENE$ were identified to act in concert with other gene defects and the CCDC88C p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,DMXL2;41022,FGFR1;69065,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"We identified four genetic variants (KCNQ1-@VARIANT$, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, @GENE$-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas @GENE$-@VARIANT$, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (@VARIANT$), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, @VARIANT$). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of @GENE$ (c.1823-1G>C) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX1 and -2;53905;50506,DUOX1;68136,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,0
"Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and p.Tyr283His) or reported at rare frequencies (p.Gln106Arg, at 0.2%; @VARIANT$, at 0.0008%; p.Arg262Gln at 0.2%; and @GENE$ @VARIANT$ at 0.0008%). Discussion The overall prevalence of GNRHR mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies. Four patients had biallelic mutations (including two patients with a novel frameshift deletion) and one patient had a digenic (@GENE$/PROKR2) heterozygous mutation.",5527354,PROKR2;16368,GNRHR;350,p.Val134Gly;tmVar:p|SUB|V|134|G;HGVS:p.V134G;VariantGroup:1;CorrespondingGene:2798;RS#:188272653;CA#:2938946,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
"In families F and K, a heterozygous missense mutation of a @VARIANT$ of @GENE$ that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/@VARIANT$ (Fig. 1l, n), respectively. In Family F, the @GENE$/235delC was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB3;7338,GJB2;2975,G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,0
"Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in  Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, GLI2/3, FGF10, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. GLI3 for EVC, FGF10, GLI2, RIPK4 and EYA1; and RET for PIK3R3 with PTPN11, which also is connected with @GENE$. RIPK4 itself is a central node for ZBTB16, CUL4B, @GENE$ and PTPN11.",6726737,RIPK4;10772,GLI3;139,p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"The @VARIANT$ variant in GJB2 occurring in complex heterozygosity with a pathogenic GJB3 variant, @VARIANT$ from SH175-389, suggests a possible digenic etiology of SNHL involving two different gap junction proteins, Cx26 and Cx31. Large deletions in GJB6 (del [GJB6-D13S1830] and del [GJB6-D13S1854]) are frequently detected in a trans configuration with a monoallelic @GENE$ mutation in certain populations. Based on these findings, it was previously hypothesized that variations in GJB2 and GJB6 in trans can cause SNHL through digenic inheritance. However, subsequent studies revealed that @GENE$ deletions result in an allele-specific lack of GJB2 mRNA expression, contributing to SNHL in a manner not resulting from digenic inheritance.",4998745,GJB2;2975,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (@GENE$). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,LQT6;71688,LQT2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"        Molecular Data All three probands carry two heterozygous variants: SQSTM1, c.1175C>T (@VARIANT$), and TIA1, c.1070A>G (@VARIANT$). None of the unaffected family members harbor both variants (Figure 1). The @GENE$ variant and @GENE$ variants have been reported in multiple databases.",5868303,TIA1;20692,SQSTM1;31202,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"The side chains of R/L566 and @VARIANT$ are shown as sticks, and the other residues are shown as lines. (D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant @GENE$ (p.R566L, p.A2282T) vector plasmids and myc-tagged WT or mutant @GENE$ (p.R297C, @VARIANT$).",7279190,FLNB;37480,TTC26;11786,A/T2282;tmVar:c|SUB|A|2282|T;HGVS:c.2282A>T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,0
"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (c.6657T>C), USH1G (c.46C>G; p.L16V) and @GENE$ (@VARIANT$).",3125325,MYO7A;219,USH2A;66151,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Out of the remaining 10 variants, 4 were detected in TANK-binding kinase 1 (TBK1), two in leucine rich repeat kinase 2 (LRRK2), one in optineurin (OPTN), one in fused in sarcoma (FUS), one in profilin 1 (@GENE$) and one in the colony stimulating factor 1 receptor (CSF1R). Importantly, when we sorted these 10 remaining variants by pathogenicity score based on CADD_Phred score, all 4 TBK1 variants and the @GENE$ variant had scores higher than 20, meaning that those substitutions are predicted to be among the 1% most deleterious substitutions in the human genome (Table 1; Figure 1a). Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:@VARIANT$; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes.",4470809,PFN1;3684,OPTN;11085,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769,0
"Our study suggests that the KCNH2-@VARIANT$ variant has pathogenic properties consistent with LQTS. @GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Proband 17 inherited @GENE$ @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,CHD7;19067,CCDC88C;18903,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"(C) Sanger sequencing confirmed a homozygous in-frame deletion (@VARIANT$) in MYD88 gene and a homozygous splice-donor mutation (@VARIANT$) in CARD9 gene. (D) Western Blot of @GENE$ and MYD88 proteins performed on PBMC, EBVB, and PHA derived T cell lines. (E) TNFalpha production by monocytes after LPS stimulation (mean +- SEM of n = 2). (F) Phenotypic analysis of iDC and @GENE$ differentiated in vitro.",6383679,CARD9;14150,mDC;7529,c.195_197delGGA;tmVar:p|DEL|195_197|G;HGVS:p.195_197delG;VariantGroup:2;CorrespondingGene:4615,c.1434+1G>C;tmVar:c|SUB|G|1434+1|C;HGVS:c.1434+1G>C;VariantGroup:0;CorrespondingGene:64170;RS#:141992399;CA#:500026,0
"There is a splicing site mutation c.1339 + 3A>T in @GENE$, inherited from her mother and a missense mutation c.4421C > T (@VARIANT$) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A3;68033,p. (Thr1474Met);tmVar:p|SUB|T|1474|M;HGVS:p.T1474M;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The presence of concomitant mutations, such as the @GENE$ @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of @GENE$/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the TCF3 T168fsX191 mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for connexin 26 (@GENE$) and @GENE$ (Cx31) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,connexin 31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1
"Using SIFT and PolyPhen, the @VARIANT$ variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and c.353A > G (@VARIANT$) in MFSD8.",7463850,SLC9A6;55971,EHMT1;11698,c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"Four genes (including AGXT2, @GENE$, SCAP, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and @GENE$-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies.",5725008,ZFHX3;21366,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of @GENE$. Direct sequence analysis showing the 497A>G (N166S) mutation (d) and WT allele (e) of @GENE$. Direct sequence analysis showing the @VARIANT$ (A194T) mutation (i and n) and WT allele (j and o) of GJB3.,2737700,GJB2;2975,GJB3;7338,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,580G>A;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in @GENE$ were identified (online supplementary table S2). While TIMP3 blocks VEGF/VEGFR2 signalling, @GENE$ modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,TIMP3;36322,RASA1;2168,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: @VARIANT$, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and @GENE$ (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,VPS13C;41188,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,c.1966C>T;tmVar:c|SUB|C|1966|T;HGVS:c.1966C>T;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
"RESULTS Mutations at the gap junction proteins Cx26 and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"While a specific genotype-phenotype correlation could not be drawn based on the combination of @GENE$ and @GENE$ mutant alleles, the IOP remained on the higher side (> 28 mmHg) in their worst affected eye along with total cupping of their optic discs (0.9:1) and poor visual acuity (ranging from mild perception of light to no light perception). Even the probands of the PCG188 and PCG200 families harboring the same TEK (@VARIANT$)::CYP1B1 (@VARIANT$) allelic combinations (Fig. 1a) had variable manifestations of IOP, corneal diameter, cup-to-disc ratio, and visual acuity at presentation.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. The TEK Q214P and @VARIANT$ alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"There is a splicing site mutation @VARIANT$ in @GENE$, inherited from her mother and a missense mutation c.4421C > T (@VARIANT$) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A3;68033,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,p. (Thr1474Met);tmVar:p|SUB|T|1474|M;HGVS:p.T1474M;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,0
"Case A was a compound heterozygote for mutations in @GENE$, carrying the p.Q235* nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1. Cases C-E carried heterozygous missense mutations in @GENE$, including the @VARIANT$ mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain.",4470809,OPTN;11085,TBK1;22742,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"Sequence alterations were detected in the @GENE$ (@VARIANT$), RYR1 (rs143445685), @GENE$ (rs138172448), and DES (@VARIANT$) genes.",6180278,COL6A3;37917,CAPN3;52,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,0
"By contrast, the expression of human @GENE$ and @GENE$, either alone or in combination, did not restore the viability of the mutant (Fig 3C), suggesting that the human orthologs have evolved in structure and function in comparison to Gcn5. As the mutated amino acid in KAT2B, @VARIANT$, is conserved in Drosophila Gcn5 (corresponding to Gcn5 F304), we re-expressed Gcn5 F304S in the Gcn5E333st hemizygous background (Gcn5 F304S). As a negative control, we re-expressed a predicted potentially damaging KAT2B variant (S502F corresponding to Gcn5 @VARIANT$) found in a homozygous state in a healthy individual from our in-house database.",5973622,KAT2A;41343,KAT2B;20834,F307;tmVar:p|Allele|F|307;VariantGroup:1;CorrespondingGene:8850,S478F;tmVar:p|SUB|S|478|F;HGVS:p.S478F;VariantGroup:13;CorrespondingGene:2648,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), @GENE$ (NM_130459.3: c.568C>T, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,TOR2A;25260,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,0
"a) A single run of homozygosity as a result of homozygosity mapping shared by all seven affected patients between @VARIANT$ and rs11808053 confirming linkage analysis. In addition, a total of 24 unaffected family members displayed no homozygosity for this region of interest. b) Linkage analysis using a total of 17 individuals (seven affected and 10 unaffected) from the two families resulting in a peak where the maximum multipoint parametric logarithm of the odds score (pLOD MPT) was 5.28, corresponding to chromosome 1p12-q21.3 on the x-axis. c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the @GENE$ protein (c.229C>T; @VARIANT$) and d) the c.238-241delATTG (p.I80Gfs*13) in @GENE$. Mutation name is based on the full-length S100A3 (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,rs10802117;tmVar:rs10802117;VariantGroup:4;RS#:10802117,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The ADD3 @VARIANT$ and KAT2B @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. All constructs were verified by sequencing. ADD3 or @GENE$ depleted podocytes were transduced with WT or mutant @GENE$ or KAT2B lentiviral particles, respectively.",5973622,KAT2B;20834,ADD3;40893,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,0
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,GJB6;4936,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and @GENE$/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the @GENE$ T168fsX191 mutation, but not the TNFRSF13B/TACI @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 @VARIANT$ gene.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"The c.1592G>A (@VARIANT$) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in @GENE$ (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within @GENE$, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3).",6161649,MAP4K4;7442,SMAD1;21196,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2). While @GENE$ blocks VEGF/@GENE$ signalling, RASA1 modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,TIMP3;36322,VEGFR2;55639,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The @VARIANT$ missense mutation in @GENE$ has previously been reported in two affected families and considered as pathogenic. However, we found it in five of 486 control alleles from French and Maghreban populations. The @VARIANT$ missense mutation in @GENE$ seems to represent a frequent sequence variant in the Moroccan population, with an estimated carrier frequency of 0.07, and was observed in three out of 306 control alleles.",3125325,CDH23;11142,MYO7A;219,p.T1209A;tmVar:p|SUB|T|1209|A;HGVS:p.T1209A;VariantGroup:132;CorrespondingGene:64072;RS#:41281314;CA#:137387,p.Y1719C;tmVar:p|SUB|Y|1719|C;HGVS:p.Y1719C;VariantGroup:16;CorrespondingGene:4647;RS#:77625410;CA#:132375,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in ISG20L2, @VARIANT$ in SETDB1 and @VARIANT$ in @GENE$, and one novel variant in @GENE$, were identified.",6637284,S100A3;2223,S100A13;7523,rs143224912;tmVar:rs143224912;VariantGroup:2;CorrespondingGene:9869;RS#:143224912,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and @GENE$/TACI @VARIANT$ mutations are shown.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$).",5887939,CELSR1;7665,PRICKLE4;22752,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, @VARIANT$; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,p.Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Except for the @GENE$ gene variant [p.(@VARIANT$)], mutations identified in DUSP6, @GENE$, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,SEMA7A;2678,ANOS1;55445,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"@GENE$-@VARIANT$ was previously associated with a prolonged QT interval in several different populations and can alter the biophysical properties of mutant channels (current density, activation, inactivation, and recovery from inactivation) and exacerbate the IKr reduction caused by other KCNH2 mutations. KCNH2-p.K897T affects also the synchronization between depolarization and repolarization and so increases the risk of cardiac mortality. Therefore, it is a genetic modifier candidate. Finally, as reported in population studies, @GENE$-@VARIANT$ is associated with heart failure, atrial fibrillation, abnormal cardiac repolarization, and an increased risk of ventricular arrhythmia.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Sequence alterations were detected in the COL6A3 (@VARIANT$), RYR1 (rs143445685), @GENE$ (rs138172448), and @GENE$ (@VARIANT$) genes.",6180278,CAPN3;52,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK @VARIANT$ (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant @GENE$ and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 A115P and R368H showed perturbed interaction with HA-TEK. The residues E103, I148, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d). This suggested that either the N-terminal TEK domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the TEK protein, which affected a secondary @GENE$-binding site.",5953556,TEK;397,CYP1B1;68035,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"The KCNQ1-@VARIANT$ variant is currently annotated as a mutation in the Human Gene Mutation Database (HGMD) database, having been identified in other LQTS subjects. KCNH2-p.K897T was previously associated with a prolonged QT interval in several different populations and can alter the biophysical properties of mutant channels (current density, activation, inactivation, and recovery from inactivation) and exacerbate the IKr reduction caused by other KCNH2 mutations. @GENE$-p.K897T affects also the synchronization between depolarization and repolarization and so increases the risk of cardiac mortality. Therefore, it is a genetic modifier candidate. Finally, as reported in population studies, KCNE1-p.G38S is associated with heart failure, atrial fibrillation, abnormal cardiac repolarization, and an increased risk of ventricular arrhythmia. Nevertheless, in vitro studies demonstrated that the @GENE$-p.G38S variant causes only a mild reduction of the delayed rectifier K+ currents. Therefore, @VARIANT$ could be a genetic modifier, but the evidence available does not suggest it has an overt effect on the function of the KCNQ1 and KCNH2 channels.",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS2;12122,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
" Results and Discussion Results We found 18 variants in our patient, five in the NOD2, four in the IL10RA and nine in the @GENE$ genes. All variants localized respectively at the 5' and/or 3' untranslated, intronic and coding regions (Table 1). Among the variants identified in NOD2, four are known variants, and one, is a novel missense variant at the exon 9 (c.2857A > G @VARIANT$) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and rs2229113 (c.1051 G > A p.G351R), have already been described in the literature.     The three-missense variants were searched for in both parents to check their pattern of inheritance. The mother carried the three variants (K953E, S159G and @VARIANT$) observed in the patient, while the father results heterozygous only for the G351R variant (Figure 1).",3975370,IL10RB;523,IL10RA;1196,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0
"Protein structure analysis We performed protein structure analysis on the two WNT10A mutations (@VARIANT$ and p.G213S) and two novel @GENE$ mutations (@VARIANT$ and p.I312M) that were identified in this study. For @GENE$, the conservation of residues in sequences was determined to predict the influence of the two mutations.",3842385,EDA;1896,WNT10A;22525,p.R171C;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.G257R;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Except for the @GENE$ gene variant [p.(@VARIANT$)], mutations identified in @GENE$, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,SEMA7A;2678,DUSP6;55621,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"However, none of these signs were evident from metabolic work of the patient with PHKA1 @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 @VARIANT$ and @GENE$ I126V variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in RYR1 and CACNA1S are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects. Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the RYR1 p.T4823 M variant in MH. Subject R462 was diagnosed as MHS, which appeared to correlate with CACNA1S p. R498L, previously reported in a single MHS subject. However, the frequency of this variant in the general population is about 20-fold higher than the frequencies of pathogenic @GENE$ variants associated with MHS.",6072915,NDUFS8;1867,CACNA1S;37257,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"(A) The EDA mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation c.936C>G and @GENE$ mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"(E) The EDA mutation c.466C>T and @GENE$ mutation @VARIANT$ were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations @VARIANT$ in @GENE$ and c.511C>T in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,WNT10A;22525,EDA;1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,0
"Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in @GENE$ (p.K268R), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and @GENE$ were not found in 666 control alleles.",3125325,MYO7A;219,USH2A;66151,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Most had @GENE$ repeat expansion combined with another mutation (e.g. VCP R155H or @GENE$ A321V; Supplementary Table 6). A single control also had two mutations, @VARIANT$ in ALS2 and @VARIANT$ in TARDBP.",5445258,C9orf72;10137,TARDBP;7221,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"        Molecular Data All three probands carry two heterozygous variants: @GENE$, @VARIANT$ (p.Pro392Leu), and TIA1, @VARIANT$ (p.Asn357Ser). None of the unaffected family members harbor both variants (Figure 1). The @GENE$ variant and SQSTM1 variants have been reported in multiple databases.",5868303,SQSTM1;31202,TIA1;20692,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"In our study, we identified four genetic variants in three genes (@GENE$-p.R583H, KCNH2-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$).",5578023,KCNQ1;85014,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, @GENE$, APC, ZNRF3, LRP4, @GENE$, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well.",7877624,RNF43;37742,LRP5;1746,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Three independent bioinformatics algorithms, SIFT, PolyPhen-2, and MutationTaster predicted both the @VARIANT$ @GENE$ and the @VARIANT$ @GENE$ mutations as benign, suggesting that mutations in these genes are unlikely to be responsible for abnormalities found in our affected patients.",4853519,MUM1L1;51851,NUP214;38008,284G>A;tmVar:c|SUB|G|284|A;HGVS:c.284G>A;VariantGroup:1;CorrespondingGene:139221;RS#:12392298;CA#:10481871,2701C>T;tmVar:c|SUB|C|2701|T;HGVS:c.2701C>T;VariantGroup:2;CorrespondingGene:8021,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ p.P136L, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,DCTN1;3011,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Circles, female; squares, male; gray, @GENE$/TACI C104R mutation; blue @GENE$ T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 @VARIANT$ mutation, but not the TNFRSF13B/TACI C104R mutation.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The DUSP6 gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,SEMA7A;2678,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,0
"After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in ISG20L2, rs143224912 in @GENE$ and @VARIANT$ in S100A3, and one novel variant in S100A13, were identified. The ISG20L2 and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A13;7523,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
This indicates that neither p.R143W in GJB2 nor @VARIANT$ in @GENE$ contributed to SNHL in SH60-136 and that @VARIANT$ in @GENE$ was an incidentally detected variant in this subject.,4998745,WFS1;4380,GJB2;2975,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,1
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (@VARIANT$, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,g.68531T>G;tmVar:g|SUB|T|68531|G;HGVS:g.68531T>G;VariantGroup:11;CorrespondingGene:4040,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Similarly, patients 8 and 10 both had a combination of a known truncating mutation (@VARIANT$) and a known inactivating mutation (@VARIANT$ or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including @GENE$, TG, @GENE$, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,TPO;461,DUOX2;9689,p.K530X;tmVar:p|SUB|K|530|X;HGVS:p.K530X;VariantGroup:6;CorrespondingGene:50506;RS#:180671269;CA#:7538552,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,0
No significant change was observed with HA-@GENE$ @VARIANT$ with GFP-@GENE$ @VARIANT$ as compared to WT proteins (Fig. 2).,5953556,TEK;397,CYP1B1;68035,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,1
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Despite the absence of IgG detected in the supernatants of these cultures, no defect was observed in the generation of isotype switched IgG+ cells in II.2 (carrying both @GENE$/TACI @VARIANT$ and @GENE$ @VARIANT$ mutations), compared to III.2, who has neither mutation.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,1
"Compared with wild-type @GENE$ (Figure 4a), the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus lead to a reduction of structural stability. However, @GENE$ p.R1865H showed no significant influence on the RNA structure (Figure 4c,d). The MFE of SCN5A @VARIANT$ mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Notably, a CCDC141 variant (@VARIANT$) was involved in 18 pathogenic digenic combinations. The CCDC141 variant acts in an autosomal recessive inheritance mode, based on the digenic effect prediction data. For the second patient (HH12), prediction by ORVAL allowed the identification of an interesting pathogenic digenic combination between DUSP6 and SEMA7A genes, predicted as ""dual molecular diagnosis."" The SEMA7A variant p.(@VARIANT$) is novel and predicted as a VUS by Varsome. Sanger validation revealed the absence of this variant in the healthy mother. We hypothesize that disease expression in HH12 could be induced by the digenic transmission of the @GENE$ and @GENE$ variants or a monogenic inheritance involving only the SEMA7A VUS if further functional assays allow its reclassification into pathogenic.",8446458,SEMA7A;2678,DUSP6;55621,c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,gap junction protein beta 6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"   A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and @VARIANT$ (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,1
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB6;4936,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Specifically, the mother and her twin sister were heterozygous for the @GENE$ missense mutation @VARIANT$ and the @GENE$ nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings.",2900916,GGCX;639,ABCC6;55559,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,1
"GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 A115P and @VARIANT$ showed perturbed interaction with HA-TEK.",5953556,TEK;397,CYP1B1;68035,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic @VARIANT$ (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"We observed that isoproterenol could enhance the activity of LTCC in the HEK293T cells, which may be associated with the evocation of @GENE$/protein kinase A pathways by the activation of the endogenous beta2 adrenoreceptors. In summary, we investigated an extremely rare large ERS family with a high incidence of nocturnal SCD, in which we found a pathogenic mutation in CACNA1C (@VARIANT$) with loss-of-function. The penetrance was also incomplete, which was modified by a gain-of-functional @GENE$-@VARIANT$ variant and sex.",5426766,cAMP;110678,SCN5A;22738,p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"The combinatorial variation of @GENE$ @VARIANT$ (p.P642R) and SCRIB c.3323G > A (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. Location analysis of missense changes showed that @VARIANT$ was located very close to the fourth PDZ domain (1109-1192) of SCRIB. The PDZ domains of human SCRIB are required for correct localization and physical interaction with other proteins, such as the core PCP protein @GENE$, which is required for transducing PCP signals.",5966321,PTK7;43672,VANGL2;62161,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"We postulate that pro-@GENE$ is more efficiently packaged into COPII vesicles because of the SEC23A mutation, but that retrograde transport from the Golgi is perturbed when MAN1B1 is mutated, as previously suggested by. The @VARIANT$ mutation in MAN1B1 was previously shown to result in decreased MAN1B1 protein levels and to encode for an enzyme with reduced catalytic function. also showed that patients with this mutation had abnormal N-glycan remodeling. Our data are consistent with those of Rafiq et al. and Rymen et al., as we found reduced MAN1B1 protein levels and glycosylation defects in patients double homozygous for the 1000C>T MAN1B1 and the @VARIANT$ SEC23A mutations. However, although we also found reduced levels of MAN1B1 protein in fibroblasts of unaffected carriers, MAN1B1 alpha-mannosidase activity in these patients must be sufficient, because they did not have glycosylation defects. Also, we postulate that additional bands (below the expected band) of MAN1B1, found in double heterozygous and double homozygous mutant fibroblasts, may represent a novel protein product generated as a consequence of the 1000C>T @GENE$ mutation, although we cannot rule out that this band represents a deglycosylated isoform of MAN1B1.",4853519,COL1A1;73874,MAN1B1;5230,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,12000 G>C;tmVar:g|SUB|G|12000|C;HGVS:g.12000G>C;VariantGroup:14;CorrespondingGene:10484,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Four genes (including @GENE$, ZFHX3, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and AGXT2-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies.",5725008,AGXT2;12887,SCAP;8160,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The combinatorial variation of @GENE$ c.1925C > G (@VARIANT$) and @GENE$ c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,PTK7;43672,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,1
The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in @GENE$ were detected.,3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Given the reported normal function of @GENE$ L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 @VARIANT$ and SLC26A4 @VARIANT$ mutations.",7067772,pendrin;20132,EphA2;20929,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS2;12122,BBS7;12395,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Phosphorylation analysis of @GENE$ @VARIANT$ showed that this mutation caused amino acid residues near position 309 dephosphorylation. The result indicated that KCNH2 p.307_308del might impact the catalytic efficiency of protein. However, there was no significant change in protein phosphorylation for @GENE$ @VARIANT$ (Table 4).",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, @GENE$ p.R148Q, @GENE$ @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,PTK7;43672,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The presence of concomitant mutations, such as the TCF3 @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ T168fsX191 mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/@GENE$ @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of @GENE$ that causes @VARIANT$, was found in profoundly deaf probands, who were also heterozygous for @GENE$/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (@VARIANT$), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.410T>M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0