Submissions for variant NM_000335.5(SCN5A):c.5357G>A (p.Ser1786Asn)

gnomAD frequency: 0.00063  dbSNP: rs199473316

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148840	SCV000050783	likely benign	Long QT syndrome	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154835	SCV000204517	benign	not specified	2019-09-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000058775	SCV000235528	likely benign	not provided	2020-11-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20129283, 22378279, 26159999, 28988457, 30669290, 15851227, 23503384, 25923670, 16414944, 10973849, 24055113, 25637381, 27930354, 11463728, 22677073, 14753626, 28069705, 22373669, 27153395, 23861362, 30847666)
Invitae	RCV000058775	SCV000291818	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000058775	SCV000575344	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	SCN5A: PP3, BS2
Ambry Genetics	RCV000621224	SCV000737646	benign	Cardiovascular phenotype	2018-12-14	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV001842385	SCV000902959	benign	Cardiac arrhythmia	2018-04-07	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000148840	SCV000987594	uncertain significance	Long QT syndrome		criteria provided, single submitter	clinical testing
Mendelics	RCV000987199	SCV001136448	benign	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000987199	SCV001304804	uncertain significance	Brugada syndrome 1	2017-04-27	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 Laboratory Services, Illumina	RCV001144218	SCV001304805	benign	Sick sinus syndrome 1	2017-04-27	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001144219	SCV001304806	uncertain significance	Ventricular fibrillation, paroxysmal familial, type 1	2017-04-27	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 Laboratory Services, Illumina	RCV001144220	SCV001304807	uncertain significance	Progressive familial heart block, type 1A	2017-04-27	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 Laboratory Services, Illumina	RCV001144221	SCV001304808	uncertain significance	Dilated cardiomyopathy 1E	2017-04-27	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154835	SCV002041844	likely benign	not specified	2021-11-22	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.5360G>A (p.Ser1787Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00079 in 395574 control chromosomes, predominantly at a frequency of 0.02 within the Ashkenazi Jewish (ASJ) subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within ASJ control individuals in the gnomAD database is approximately 200-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism. c.5360G>A has been reported in the literature in individuals affected with Arrhythmia (Splawski_2000, Zaklyazminskaya_2013), however it was also found in several healthy controls (e.g. Kapplinger_2010, Ackerman_2004, Ng_2013, Refsgaard_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. One publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the molecular phenotype of the S1787N variant might depend upon both the splice variant background in which it is expressed and on the intracellular pH, i.e. the channel properties of the S1787N in the Q1077del background were altered under more acidic conditions (Hu_2015). These data however, do not allow convincing conclusions about the variant effect. Nine submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=2), likely benign (n=2) or benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058775	SCV000090295	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:10973849;PMID:15851227;PMID:16414944;PMID:19841300;PMID:20129283;PMID:22378279).
CSER _CC_NCGL, University of Washington	RCV000148840	SCV000190581	likely benign	Long QT syndrome	2014-06-01	no assertion criteria provided	research
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000474591	SCV000541079	pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia		flagged submission	research