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Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combinat... | 4,293,318 | SOD1;392 | TARDBP;7221 | p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390 | p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953 | 0no label |
To investigate the role of @GENE$ 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 mis... | 2,737,700 | 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 | 0no label |
The study revealed @GENE$ gene mutations in a majority of our cohort (33%), in accordance with the percentages already reported in the literature. Interestingly, we found just one patient with variants in BBS1, the most frequently detected gene in BBS patients. We identified a novel variant in BBS1 patient #10 c.1285du... | 6,567,512 | BBS10;49781 | BBS2;12122 | p.(Arg429Profs*72);tmVar:p|FS|R,P|429|RO|72;HGVS:p.R,P429ROfsX72;VariantGroup:28;CorrespondingGene:582 | p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583 | 0no label |
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 @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 ... | 5,887,939 | CELSR1;7665 | PRICKLE4;22752 | c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970 | c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776 | 0no label |
(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. | 4,998,745 | gap junction protein beta 2;2975 | GJB3;7338 | 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 | 0no label |
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: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees. De... | 6,081,235 | TRPV4;11003 | CAPN11;21392 | p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615 | p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011 | 0no label |
Co-segregation of TEK p.I148T and CYP1B1 @VARIANT$ was observed in two pedigrees and only a representative pedigree is shown. b Chromatograms of the four probands (lower panel) harboring the four different heterozygous @GENE$ mutations. The site of nucleotide change is indicated by an arrow, compared to the correspondi... | 5,953,556 | TEK;397 | CYP1B1;68035 | p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 | p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 | 0no label |
CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ @VARIANT$ and @GENE$ @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. | 8,739,608 | KCNH2;201 | SCN5A;22738 | p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 | p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 | 11 |
Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 @VARIANT$, CELSR1 p... | 5,966,321 | SCRIB;44228 | CELSR1;7665 | p.Q2924H;tmVar:p|SUB|Q|2924|H;HGVS:p.Q2924H;VariantGroup:1;CorrespondingGene:9620;RS#:200116798;CA#:10292663 | p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763 | 0no label |
In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in @GENE$ 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/VEGFR2 signalling, RASA1 modulates differentiat... | 6,161,649 | RASA1;2168 | TIMP3;36322 | 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 | 0no label |
SCAP-c.3035C>T (p.Ala1012Val) variant impaired the negative feedback mechanism of cholesterol synthesize in H293T cell lines SCAP-c.3035C>T (@VARIANT$) variant was introduced into H293T cell lines by CRISPR-Cas9 methodology. After incubated with medium A (as described in the materials and methods section) for 6 hours, ... | 5,725,008 | SCAP;8160 | AGXT2;12887 | p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937 | c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745 | 0no label |
We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (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 2... | 6,567,512 | BBS7;12395 | BBS6;10318 | c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582 | c.1235G > T;tmVar:c|SUB|G|1235|T;HGVS:c.1235G>T;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386 | 0no label |
The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene.... | 6,707,335 | GRN;1577 | SQSTM1;31202 | R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049 | P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372 | 0no label |
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 stop codon in position... | 6,567,512 | BBS2;12122 | BBS7;12395 | c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212 | Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386 | 0no label |
Based on both clinical and laboratory quantification, it appears neither the @GENE$/TACI @VARIANT$ mutation nor the @GENE$ @VARIANT$ mutation alone is sufficient to cause the complete, severe CVID-like disorder and SLE observed in the proband. | 5,671,988 | 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 | 11 |
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and @GENE$/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3). | 3,888,818 | KAL1;55445 | NELF;10648 | p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 | c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871 | 0no label |
Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-@GENE$ @VARIANT$ and HA-TEK Q214P, respectively, was significantly diminished. GFP-@GENE$ @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). | 5,953,556 | TEK;397 | CYP1B1;68035 | E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 | R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 | 0no label |
SCN5A @VARIANT$ and @GENE$ p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for @GENE$ and KCNH2 mutations. KCNH2 @VARIANT$ and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing. | 8,739,608 | KCNH2;201 | SCN5A;22738 | p.R1865;tmVar:p|Allele|R|1865;VariantGroup:1;CorrespondingGene:6331;RS#:370694515 | p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 | 0no label |
(C) Sanger sequencing confirmed a homozygous in-frame deletion (@VARIANT$) in MYD88 gene and a homozygous splice-donor mutation (@VARIANT$) in @GENE$ gene. (D) Western Blot of CARD9 and @GENE$ proteins performed on PBMC, EBVB, and PHA derived T cell lines. | 6,383,679 | CARD9;14150 | MYD88;1849 | 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 | 0no label |
Therefore, in this study, SCN5A p.R1865H 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 @GENE$ p.307_308del and SCN5A p.R1865H increased the risk of... | 8,739,608 | 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 | 0no label |
(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and @VARIANT$, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consist... | 3,975,370 | IL10RA;1196 | NOD2;11156 | c.1051A > G;tmVar:c|SUB|A|1051|G;HGVS:c.1051A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322 | K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561 | 0no label |
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 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which resul... | 3,842,385 | 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 | Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 | 0no label |
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 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which resul... | 3,842,385 | WNT10A;22525 | EDA;1896 | 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 | 0no label |
We identified a novel variant in the @GENE$ gene (c.2857A > G @VARIANT$) and two already described missense variants in the @GENE$ gene (S159G and @VARIANT$). | 3,975,370 | NOD2;11156 | IL10RA;1196 | p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561 | G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561 | 0no label |
@GENE$ and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina. In patient AVM144, the compound heterozygous variants @VARIANT$ and @VARIANT$ (p.Ser334Thr) were identified in @GENE$ (table 2). | 6,161,649 | DSCAML1;79549 | PTPN13;7909 | c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588 | c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566 | 0no label |
The @VARIANT$ (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in exon 3 of @GENE$ were detected. These mutations were not found in his father's genome, but because his mother's DNA sample was unavailable, the origin of the mutant alleles was not clear (Fig. 2F). All novel m... | 3,842,385 | EDA;1896 | WNT10A;22525 | p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657 | G213;tmVar:c|Allele|G|213;VariantGroup:4;CorrespondingGene:80326;RS#:147680216 | 0no label |
WES revealed heterozygous mutations in two genes known to affect hypothalamic and pituitary development: @VARIANT$;p.R85C in @GENE$ (MIM 607123; NM_144773.2; rs141090506) inherited from an unaffected mother and c.1306A>G;@VARIANT$ in @GENE$ (MIM 606417; NM_018117.11; rs34602786) inherited from an unaffected fathe... | 5,505,202 | PROKR2;16368 | WDR11;41229 | c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601 | p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694 | 11 |
Hence, priority should be given to identifying the TCF3 @VARIANT$ mutation for preimplantation genetic diagnosis and/or chorionic villus sampling. Based on both clinical and laboratory quantification, it appears neither the @GENE$/TACI @VARIANT$ mutation nor the @GENE$ T168fsX191 mutation alone is sufficient to cause t... | 5,671,988 | TNFRSF13B;49320 | TCF3;2408 | 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 | 0no label |
Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A). The LRP6 @VARIANT$ mutation is a rare variant with an MAF of 0.0024 in E... | 8,621,929 | LRP6;1747 | WNT10A;22525 | c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 | c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188 | 0no label |
The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in ex... | 3,842,385 | WNT10A;22525 | EDA;1896 | c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 | c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 | 0no label |
Because charged residues are important for proteins trafficking, the @VARIANT$ may result in accumulation of the Cx31 protein in intracellular compartments such as the Golgi apparatus or in other sites such as the endoplasmic reticulum or lysosomes. The A194T substitution might cause conformational changes within the C... | 2,737,700 | Cx31;7338 | Cx32;137 | A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 | F193C;tmVar:p|SUB|F|193|C;HGVS:p.F193C;VariantGroup:15;CorrespondingGene:2706 | 0no label |
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 g... | 6,707,335 | 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 | 0no label |
21 Additional gene reportedly linked to tumorigenesis include RYR3, 22 @GENE$, 23 @GENE$, 24 and CAPN9. 25 The RYR3 (NM_001036: @VARIANT$, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, ... | 7,689,793 | EBNA1BP2;4969 | TRIP6;37757 | c.7812C > G;tmVar:c|SUB|C|7812|G;HGVS:c.7812C>G;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988 | p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452 | 0no label |
This analysis indicated that the @GENE$ variant @VARIANT$ (rs138172448), which results in a p.Val555Ile change, and the @GENE$ gene variant c.656C>T (@VARIANT$), which results in a p.Thr219Ile change, are both predicted to be damaging. | 6,180,278 | CAPN3;52 | DES;56469 | c.1663G>A;tmVar:c|SUB|G|1663|A;HGVS:c.1663G>A;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461 | rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249 | 0no label |
In our study, we identified four genetic variants in three genes (@GENE$-p.R583H, @GENE$-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$). | 5,578,023 | KCNQ1;85014 | KCNH2;201 | p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 | p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 | 0no label |
In our study, we identified four genetic variants in three genes (@GENE$-p.R583H, KCNH2-p.C108Y, @GENE$-@VARIANT$, and KCNE1-@VARIANT$). | 5,578,023 | KCNQ1;85014 | KCNH2;201 | p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162 | p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 | 0no label |
Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). | 2,737,700 | GJB3;7338 | GJB2;2975 | A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 | 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 | 0no label |
Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequ... | 6,637,284 | S100A3;2223 | S100A13;7523 | c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 | p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284 | 11 |
Missense variants in the NEFH gene were detected in four patients: the T338I variant in two cases and the R148P and @VARIANT$ variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and R148P variants affect the conserved ce... | 6,707,335 | GRN;1577 | SQSTM1;31202 | P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372 | C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519 | 0no label |
Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls. | 2,737,700 | GJB2;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 | 0no label |
Recently, rare heterozygous alleles in the angiopoietin receptor-encoding gene @GENE$ were implicated in PCG. We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous TEK mutations. Our investigations revealed 12 rare heterozygo... | 5,953,556 | TEK;397 | CYP1B1;68035 | p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 | p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 | 0no label |
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 NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3). | 3,888,818 | 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 | 0no label |
Subsequently many genes encoding folate pathway enzymes, transporters and receptors have been studied with mostly inconsistent findings.7 More recently, several candidate variants were identified in @GENE$ and @GENE$, 2 of the genes constituting the mitochondrial GCS.10, 32 In the present study, we identified a novel m... | 5,887,939 | AMT;409 | GLDC;141 | c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990 | c.2203G>T;tmVar:c|SUB|G|2203|T;HGVS:c.2203G>T;VariantGroup:3;CorrespondingGene:2731;RS#:143119940;CA#:4980332 | 0no label |
The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely wit... | 6,637,284 | SETDB1;32157 | S100A13;7523 | c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;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 | 0no label |
Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and SCRIB @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, @GEN... | 5,966,321 | PTK7;43672 | CELSR1;7665 | p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256 | p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676 | 0no label |
Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (@VARIANT$), 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.Gly505Se... | 7,463,850 | EHMT1;11698 | MFSD8;115814 | p.Leu593Phe;tmVar:p|SUB|L|593|F;HGVS:p.L593F;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857 | p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496 | 0no label |
Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.103... | 7,877,624 | EDN3;88 | MITF;4892 | c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 | p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 | 0no label |
@GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single... | 4,998,745 | DFNB1;2975 | GJB3;7338 | 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 | 0no label |
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 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which resul... | 3,842,385 | 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 | 0no label |
We identified a novel variant in the @GENE$ gene (c.@VARIANT$ p.K953E) and two already described missense variants in the @GENE$ gene (@VARIANT$ and G351R). | 3,975,370 | NOD2;11156 | IL10RA;1196 | 2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322 | S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561 | 11 |
RESULTS Mutations at the gap junction proteins @GENE$ 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 ... | 2,737,700 | Cx26;2975 | Cx31;7338 | 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 | 0no label |
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$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, w... | 3,842,385 | EDA;1896 | WNT10A;22525 | Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 | c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 | 0no label |
There is a splicing site mutation c.1339 + 3A>T in @GENE$, inherited from her mother and a missense mutation c.4421C > T (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygou... | 6,565,573 | COL4A5;133559 | COL4A4;20071 | Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204 | c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286 | 0no label |
The patient carried a heterozygous variant of unknown significance in @GENE$, p.(@VARIANT$), defined as likely pathogenic in ClinVar, and a missense variant p.(@VARIANT$) in PMM2, classified as likely pathogenic. Recessive mutations in PMM2 were reported as associated to hyperinsulinemic hypoglycemia (HI) and @GENE$ (C... | 7,224,062 | PKHD1;16336 | PKD;55680 | His3124Tyr;tmVar:p|SUB|H|3124|Y;HGVS:p.H3124Y;VariantGroup:17;CorrespondingGene:5314 | Gly42Arg;tmVar:p|SUB|G|42|R;HGVS:p.G42R;VariantGroup:5;CorrespondingGene:5373;RS#:755402538;CA#:7893895 | 0no label |
Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARI... | 7,877,624 | TYRO3;4585 | MITF;4892 | 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 | 0no label |
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, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hear... | 2,737,700 | GJB2;2975 | GJB3;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 | 0no label |
Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in tw... | 6,081,235 | GNA14;68386 | TRPV4;11003 | p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 | c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 | 0no label |
In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (@VARIANT$) were identified in @GENE$ (table 2). Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In... | 6,161,649 | PTPN13;7909 | ENG;92 | c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588 | p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566 | 0no label |
Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK... | 5,887,939 | CELSR1;7665 | FZD6;2617 | c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808 | c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776 | 0no label |
Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ @VARIANT$), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). | 5,887,939 | PRICKLE4;22752 | DVL3;20928 | c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865 | c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 | 0no label |
M2, @GENE$: p.(E387K). M3, CYP1B1: @VARIANT$. M4, PITX2: p.(P179T). M5, @GENE$: @VARIANT$. Arrows show the index cases. | 6,338,360 | CYP1B1;68035 | PITX2;55454 | p.(E173*);tmVar:p|SUB|E|173|*;HGVS:p.E173*;VariantGroup:11;CorrespondingGene:1545 | p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139 | 0no label |
Ebermann et al. described a USH2 patient with "digenic inheritance." a heterozygous truncating mutation in GPR98, and a truncating heterozygous mutation in PDZ domain-containing 7 (@GENE$), which is reported to be a cause of USH. Our USH1 patient (Case #4) had segregated MYO7A:p.Ala771Ser and PCDH15:@VARIANT$. ... | 3,949,687 | PDZD7;129509 | PCDH15;23401 | c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348 | p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351 | 0no label |
To investigate the role of @GENE$ 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 misse... | 2,737,700 | GJB3;7338 | GJB2;2975 | 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 | 0no label |
Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 @VARIANT$ and GFP-@GENE$ E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%). | 5,953,556 | CYP1B1;68035 | TEK;397 | A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 | I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 | 0no label |
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 @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037... | 7,877,624 | SOX10;5055 | MITF;4892 | c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 | p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 | 0no label |
c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the @VARIANT$ of the @GENE$ protein (c.229C>T; p.R77C) and d) the @VARIANT$ (p.I80Gfs*13) in @GENE$. Mutation name is based on the full-length S100A3 (NM_00296... | 6,637,284 | S100A3;2223 | S100A13;7523 | arginine residue to cysteine at position 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 | c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284 | 11 |
The DUSP6 gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of @GENE$ were extra... | 8,446,458 | SEMA7A;2678 | PROKR2;16368 | c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072 | c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482 | 0no label |
Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARI... | 7,877,624 | EDN3;88 | TYRO3;4585 | p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 | c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 | 0no label |
These results suggest an important role of ephrin-B2 as an inducer of @GENE$ endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1. Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA... | 7,067,772 | EphA2;20929 | ephrin-B2;3019 | A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306 | S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 | 0no label |
A total of 2 novel variants, @VARIANT$ and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 @GENE$ variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The TSHR variant p.R450H was a recurrent inactivating mu... | 7,248,516 | TSHR;315 | DUOXA2;57037 | p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885 | p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605 | 0no label |
Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.10... | 7,877,624 | TYRO3;4585 | MITF;4892 | p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 | c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 | 0no label |
The proband, who had @GENE$ p.(Asn1075Ser), p.(@VARIANT$), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth. | 8,621,929 | LRP6;1747 | WNT10A;22525 | Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897 | Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 | 11 |
Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previou... | 6,371,743 | NRXN1;21005 | NRXN2;86984 | p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 | c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001 | 11 |
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and @GENE$/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). | 3,888,818 | NELF;10648 | TACR3;824 | 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 | 0no label |
Cardiac Phenotype: A @GENE$/NFATC1 Genetic Interaction The cardiac phenotype in the indexed-family is divided into two: a mild VSD not requiring any intervention and a severe TOF-like phenotype that required major intervention (Figure 1). We sought that differential variants inherited from the father would cont... | 5,611,365 | FOXC1;20373 | OBSCN;70869 | p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033 | p.R222Q;tmVar:p|SUB|R|222|Q;HGVS:p.R222Q;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692 | 0no label |
The proband's mother and aunt, also manifesting with PXE-like skin changes, were heterozygous carriers of a missense mutation (@VARIANT$) in @GENE$ and a null mutation (@VARIANT$) in the @GENE$ gene, suggesting digenic nature of their skin findings. | 2,900,916 | 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 | 11 |
The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ 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 IL... | 6,637,284 | ISG20L2;12814 | 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 | 0no label |
Moreover, mutations in residues close to @VARIANT$ and A194 identified in the families reported here, namely, M163L, R165W, F191L, and @VARIANT$ in Cx26 as well as F193C, S198F and G199R in Cx32, have been reported previously in patients with hearing impairment. Interestingly, mutations identified in patients with the ... | 2,737,700 | Cx26;2975 | GJB3;7338 | N166;tmVar:p|Allele|N|166;VariantGroup:0;CorrespondingGene:2707;RS#:121908851 | A197S;tmVar:p|SUB|A|197|S;HGVS:p.A197S;VariantGroup:3;CorrespondingGene:2706;RS#:777236559 | 0no label |
DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in MAN1B1, @VARIANT$. The affected patients presented with moderate global developmental delay, tall s... | 4,853,519 | MAN1B1;5230 | SEC23A;4642 | 1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384 | 1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197 | 0no label |
RESULTS Mutations at the gap junction proteins @GENE$ 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 ... | 2,737,700 | Cx26;2975 | Cx31;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 | 11 |
Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037... | 7,877,624 | SNAI2;31127 | TYRO3;4585 | p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 | p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 | 0no label |
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3). | 3,888,818 | KAL1;55445 | NELF;10648 | 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 | 0no label |
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. ... | 6,098,846 | TPO;461 | TG;2430 | 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 | 0no label |
Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. | 6,081,235 | CACNA1A;56383 | ATP2A3;69131 | p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346 | p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615 | 0no label |
Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 @VARIANT$ and SCRIB c.3979G>A). One patient (f93-80) had a novel PT... | 5,887,939 | FZD;8321;8323 | FAT4;14377 | c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865 | c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903 | 0no label |
Altogether, the results suggest that @GENE$ @VARIANT$ is a loss-of-function mutation in Drosophila. KAT2B F307S but not @GENE$ @VARIANT$ causes cardiac defects in Drosophila Since the presence of SRNS and heart defects in family A was the main phenotypic difference from the other families, we looked more specifically i... | 5,973,622 | KAT2B;20834 | ADD3;40893 | F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850 | E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787 | 0no label |
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. Th... | 6,707,335 | 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 | 0no label |
The @VARIANT$ mutation would be predicted to generate a nonfunctional @GENE$ enzyme, and its digenic inheritance alongside the homozygous DUOX2 @VARIANT$ will likely result in complete absence of functional DUOX isoenzyme in our patients. It has been speculated that DUOX1 upregulation in the context of DUOX2 loss of fu... | 5,587,079 | DUOX1;68136 | DUOX2;9689 | 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 | 0no label |
CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 @VARIANT$ and @GENE$ @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function... | 8,739,608 | SCN5A;22738 | Kv11.1;201 | p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 | p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 | 0no label |
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of @GENE$). | 3,888,818 | KAL1;55445 | TACR3;824 | c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137 | p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 | 0no label |
Moreover, patients carrying a @GENE$ @VARIANT$ mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the di... | 6,359,299 | LAMA4;37604 | MYBPC3;215 | Pro943Leu;tmVar:p|SUB|P|943|L;HGVS:p.P943L;VariantGroup:5;CorrespondingGene:3910;RS#:387907365;CA#:143749 | L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954 | 0no label |
Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates ... | 3,426,548 | PROK2;9268 | FGFR1;69065 | p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335 | p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481 | 0no label |
One fetus with anencephaly (735F97) carried a rare missense mutation (c.2852C>A; @VARIANT$; rs147472391) in glycine decarboxylase (GLDC), which was previously reported as one of the causative mutated alleles in a compound heterozygous patient with the autosomal recessive disorder, non-ketotic hyperglycinemia (NKH, OMIM... | 5,887,939 | GLDC;141 | cystathionine gamma-lyase;1432 | p.Ser951Tyr;tmVar:p|SUB|S|951|Y;HGVS:p.S951Y;VariantGroup:20;CorrespondingGene:2731;RS#:147472391;CA#:4980035 | rs28941785;tmVar:rs28941785;VariantGroup:30;CorrespondingGene:1491;RS#:28941785 | 0no label |
The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, 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 (c.511C>T) of the coding sequence in ... | 3,842,385 | 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 | c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 | 0no label |
This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were iden... | 6,161,649 | ENG;92 | BMP;55955 | c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380 | c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588 | 0no label |
Here, we have demonstrated that the @GENE$ @VARIANT$ 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. | 5,671,988 | 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 | 11 |
Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for REEP4 c.109C>T. (b) Electropherograms of unaffected family member (II-2) and subject with @GENE$ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of @VARIANT$ among vertebrates @G... | 6,081,235 | BSP+;3644 | TOR2A;25260 | Arg37;tmVar:p|Allele|R|37;VariantGroup:10;CorrespondingGene:80346;RS#:780399718 | c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615 | 0no label |
Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) 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... | 3,842,385 | EDA;1896 | WNT10A;22525 | 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 | c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 | 0no label |
In this study, we speculated that, during the repolarization phase, the inadequate inward current caused by the detrimental CACNA1C-Q1916R mutation might be partly compensated by the persistent inward tail INa produced by the @GENE$-@VARIANT$ channel. That may be how SCN5A-R1193Q plays a protective role against the det... | 5,426,766 | SCN5A;22738 | CACNA1C;55484 | R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 | Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963 | 0no label |
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and @VARIANT$; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). | 3,888,818 | 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 | 0no label |
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