Submissions for variant NM_000335.5(SCN5A):c.874G>A (p.Gly292Ser)

gnomAD frequency: 0.00002  dbSNP: rs199473085

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000987234	SCV001136484	uncertain significance	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842416	SCV001354419	uncertain significance	Cardiac arrhythmia	2022-12-19	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 292 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 15277732), in an individual affected with long QT syndrome (PMID: 30246897), and in an individual affected with dilated cardiomyopathy (PMID: 31521807). This variant has also been identified in 10/280512 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003656625	SCV001507583	uncertain significance	not provided	2024-09-29	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 292 of the SCN5A protein (p.Gly292Ser). This variant is present in population databases (rs199473085, gnomAD 0.04%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 15277732, 30246897, 31521807). ClinVar contains an entry for this variant (Variation ID: 68053). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 21840964, 25261036). 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	RCV002498348	SCV002799609	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	2022-03-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842416	SCV004815056	uncertain significance	Cardiac arrhythmia	2024-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 292 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 15277732), in an individual affected with long QT syndrome (PMID: 30246897), and in an individual affected with dilated cardiomyopathy (PMID: 31521807). This variant has also been identified in 10/280512 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	RCV004019066	SCV004944540	likely benign	Cardiovascular phenotype	2024-10-31	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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV003656625	SCV005198175	uncertain significance	not provided	2022-06-16	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058856	SCV000090376	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:15277732). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.