Submissions for variant NM_000335.5(SCN5A):c.5800G>A (p.Gly1934Ser)

gnomAD frequency: 0.00001  dbSNP: rs199473637

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003539786	SCV000812435	uncertain significance	not provided	2025-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1935 of the SCN5A protein (p.Gly1935Ser). This variant is present in population databases (rs199473637, gnomAD 0.01%). This missense change has been observed in individuals with dilated cardiomyopathy, long QT syndrome, suspected or confirmed Brugada syndrome, and/or unexplained sudden death (PMID: 16267250, 18508782, 20129283, 27816319, 31534214). ClinVar contains an entry for this variant (Variation ID: 68011). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 16267250, 17854786). 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.
Fulgent Genetics, Fulgent Genetics	RCV000764500	SCV000895571	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	RCV001842395	SCV000913631	uncertain significance	Cardiac arrhythmia	2023-10-17	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1935 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). A functional study has shown that the mutant cardiac sodium channel exhibited enhanced slow inactivation compared with the wild-type channel (PMID: 16267250). This variant has been reported in individuals affected with Brugada syndrome (PMID: 16267250, 20129283), long QT syndrome (PMID: 27816319), or dilated cardiomyopathy (PMID: 31983221), as well as in an individual from a family with a possible sudden arrhythmic death syndrome (PMID: 18508782). This variant has been identified in 7/248912 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	RCV003298123	SCV003997043	likely benign	Cardiovascular phenotype	2023-06-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
All of Us Research Program, National Institutes of Health	RCV001842395	SCV004832493	uncertain significance	Cardiac arrhythmia	2023-12-01	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058807	SCV000090327	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:16267250;PMID:18508782;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.