ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs199473086
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Total submissions: 7
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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.
Invitae 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)
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.

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