Submissions for variant NM_000335.5(SCN5A):c.880G>A (p.Val294Met)

gnomAD frequency: 0.00004  dbSNP: rs199473086

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455194	SCV000540292	uncertain significance	not specified	2016-10-20	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 BrS proband (PMID 11901046) and as secondary finding in a WES case.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000998027	SCV000760271	uncertain significance	not provided	2023-06-24	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 21840964, 25261036). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 68054). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 11901046, 31737537). This variant is present in population databases (rs199473086, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 294 of the SCN5A protein (p.Val294Met).
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000678952	SCV000805167	uncertain significance	Long QT syndrome 3	2018-04-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765741	SCV000897109	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842417	SCV000913649	uncertain significance	Cardiac arrhythmia	2023-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 294 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental studies have shown that this variant may cause reduced sodium channel currents (PMID: 21840964, 25261036). This variant has been reported in an individual affected with Brugada syndrome (PMID: 11901046), and in an individual suspected of having long QT syndrome (PMID: 31737537). This variant has been identified in 8/280450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV000998027	SCV001804355	uncertain significance	not provided	2021-04-01	criteria provided, single submitter	clinical testing	Reported in association with arrhythmia (Priori et al., 2000; Marschall et al., 2019); however, detailed clinical information was not provided; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 68054; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate a small but significant reduction of sodium current density in V294M SCN5A channels, though, it is not known whether this finding is physiologically relevant in vivo (Shinlapawittayatorn et al., 2011); This variant is associated with the following publications: (PMID: 33221895, 11901046, 14961552, 11076825, 21840964, 14753626, 27711072, 30662450, 31737537)
All of Us Research Program, National Institutes of Health	RCV001842417	SCV004820390	uncertain significance	Cardiac arrhythmia	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 294 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental studies have shown that this variant may cause reduced sodium channel currents (PMID: 21840964, 25261036). This variant has been reported in an individual affected with Brugada syndrome (PMID: 11901046), and in an individual suspected of having long QT syndrome (PMID: 31737537). This variant has been identified in 8/280450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004019067	SCV004944541	uncertain significance	Cardiovascular phenotype	2020-02-19	criteria provided, single submitter	clinical testing	The c.880G>A (p.V294M) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 880, causing the valine (V) at amino acid position 294 to be replaced by a methionine (M). In silico prediction is conflicting:_x000D_ The p.V294M alteration is predicted to be possibly damaging by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058857	SCV000090377	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11901046;PMID:11076825). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.