ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3781G>A (p.Gly1261Ser) (rs137854616)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000058602 SCV000825694 uncertain significance Brugada syndrome 2018-06-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1262 of the SCN5A protein (p.Gly1262Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs137854616, ExAC 0.01%). This variant has been reported in a family affected with Brugada syndrome (PMID: 15338453), in an individual referred for Brugada genetic testing (PMID: 20129283), and individuals with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 27554632). ClinVar contains an entry for this variant (Variation ID: 9399). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000755698 SCV000883130 uncertain significance Long QT syndrome 3 2018-11-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779407 SCV000916019 uncertain significance SCN5A-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The SCN5A c.3784G>A (p.Gly1262Ser) missense variant has been reported in two studies in which it is found in a total of seven individuals in a heterozygous state, including in one proband with Brugada syndrome, the proband's affected brother and as yet two unaffected children, in one additional unrelated individual with Brugada syndrome, in one individual diagnosed with dilated cardiomyopathy, and in one individual diagnosed with hypertrophic cardiomyopathy (Shin et al. 2004; Priganc et al. 2016). The p.Gly1262Ser variant was absent from 352 control chromosomes, but is reported at a frequency of 0.00013 in the South Asian population of the Genome Aggregation Database. Based on the evidence, the p.Gly1262Ser variant is classified as a variant of uncertain significance but suspicious for pathogenicity for SCN5A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Clinical Services Laboratory,Illumina RCV001146725 SCV001307479 uncertain significance Progressive familial heart block, type 1A 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001146726 SCV001307480 uncertain significance Paroxysmal familial ventricular fibrillation 1 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000755698 SCV001307481 uncertain significance Long QT syndrome 3 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001146727 SCV001307482 uncertain significance Sick sinus syndrome 1, autosomal recessive 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000010001 SCV001422293 likely pathogenic Brugada syndrome 1 2020-02-21 criteria provided, single submitter clinical testing
OMIM RCV000010001 SCV000030222 pathogenic Brugada syndrome 1 2004-01-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058602 SCV000090122 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:15338453;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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