Submissions for variant NM_000335.5(SCN5A):c.2497G>A (p.Gly833Arg)

gnomAD frequency: 0.00001  dbSNP: rs45475899

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058503	SCV000235409	uncertain significance	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Identified in association with LQTS in published literature (Hedley et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 26332594, 28988457, 22581653, 32470535, 19862833, 32533946, 30079003)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239085	SCV000297008	uncertain significance	Long QT syndrome 3; Brugada syndrome	2015-08-05	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000058503	SCV000339205	uncertain significance	not provided	2016-02-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058503	SCV001010477	likely benign	not provided	2024-11-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000987215	SCV001136464	uncertain significance	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842315	SCV001354761	uncertain significance	Cardiac arrhythmia	2023-10-26	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 833 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved transmembrane domain (a.a. 718-938). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 32470535) and in another individual affected with dilated cardiomyopathy (PMID: 34486814). Both of these two individuals also carried another pathogenic truncation variant that could explain the observed phenotypes. This variant has been identified in 37/251112 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	RCV002426618	SCV002741859	uncertain significance	Cardiovascular phenotype	2023-11-16	criteria provided, single submitter	clinical testing	The p.G833R variant (also known as c.2497G>A), located in coding exon 15 of the SCN5A gene, results from a G to A substitution at nucleotide position 2497. The glycine at codon 833 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been seen in a Brugada syndrome and long QT syndrome cohort, as well as in a sudden unexplained death cohort (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95; Son MJ et al. J Korean Med Sci, 2018 Aug;33:e200). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000058503	SCV003821333	uncertain significance	not provided	2020-12-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842315	SCV004815762	uncertain significance	Cardiac arrhythmia	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 833 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved transmembrane domain (a.a. 718-938). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 32470535) and in another individual affected with dilated cardiomyopathy (PMID: 34486814). Both of these two individuals also carried another pathogenic truncation variant that could explain the observed phenotypes. This variant has been identified in 37/251112 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058503	SCV000090023	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19862833).
CSER _CC_NCGL, University of Washington	RCV000148860	SCV000190604	uncertain significance	Long QT syndrome	2014-06-01	no assertion criteria provided	research