Submissions for variant NM_000335.5(SCN5A):c.1127G>A (p.Arg376His)

gnomAD frequency: 0.00003  dbSNP: rs199473101

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182960	SCV000235357	pathogenic	not provided	2023-08-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant results in a significant reduction of the inward sodium current (Rossenbacker et al., 2004; Shinlapawittayatorn et al., 2011; Detta et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17512504, 20129283, 28341781, 34461752, 15851228, 23414114, 25194972, 18378609, 16344400, 23671135, 27930701, 21840964, 31737537, 30193851, 30662450, 29709101, 33164571, 33131149, 30203441, 34495297, 24295898)
Ambry Genetics	RCV000617435	SCV000737601	likely pathogenic	Cardiovascular phenotype	2024-01-10	criteria provided, single submitter	clinical testing	The p.R376H variant (also known as c.1127G>A), located in coding exon 8 of the SCN5A gene, results from a G to A substitution at nucleotide position 1127. The arginine at codon 376 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with Brugada syndrome (BrS; Rossenbacker T et al. Heart Rhythm. 2004;1(5):610-5; Frustaci A et al. Circulation. 2005;112(24):3680-7; Kapplinger JD et al. Heart Rhythm. 2010;7(1):33-46). It has also been identified in an individual with atrial fibrillation (Darbar D et al. Circulation. 2008;117(15):1927-35) and in families with a history of sudden death (Papadakis M et al. Circ Arrhythm Electrophysiol. 2013;6(3):588-96; Wong LC et al. Circ Arrhythm Electrophysiol. 2014;7(5):800-6). Additionally, p.R376H has been shown to disrupt protein function, resulting in reduced sodium channel current (Rossenbacker T et al. Heart Rhythm 2004;1(5):610-5; Shinlapawittayatorn K et al. Heart Rhythm 2011; 8(3):455-62; Detta N et al. Int. J. Cardiol. 2014; 170(3):e63-5; Peters CH et al. Mol. Biol. 2016;120(1-3):77-88). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000182960	SCV000760186	pathogenic	not provided	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 376 of the SCN5A protein (p.Arg376His). This variant is present in population databases (rs199473101, gnomAD 0.004%). This missense change has been observed in individuals with Brugada syndrome (PMID: 15851228, 16344400, 18378609, 20129283, 23671135, 25194972, 27930701, 28341781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67639). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15851228, 21840964, 24295898). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001842271	SCV001359848	pathogenic	Cardiac arrhythmia	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 376 of the SCN5A protein. This variant is found within the highly conserved pore-forming region of transmembrane domain DI (a.a. 277-389). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). Functional studies have shown that this variant significantly reduces sodium channel currents (PMID: 15851228, 21840964, 24295898, 26713557). This variant has shown a highly variable phenotypic presentation ranging from Brugada syndrome to conduction disease in 9 members from a single family (PMID: 15851228). This variant has been reported in multiple other individuals affected with Brugada syndrome or referred for Brugada syndrome genetic testing (PMID: 16344400, 20129283, 28341781, 29709101) in an individual affected with atrial fibrillation (PMID: 18378609) and in individuals affected with sudden death (PMID: 23671135, 25194972, 27930701). This variant has been identified in 2/247596 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000182960	SCV002020029	pathogenic	not provided	2020-02-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498339	SCV002814864	pathogenic	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	2021-11-12	criteria provided, single submitter	clinical testing
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV003457639	SCV004190147	likely pathogenic	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; Atrial fibrillation, familial, 10	2021-11-11	criteria provided, single submitter	clinical testing	The c.1127G>A variant in theSCN5A gene is a heterozygous missense variant, which results in the substitution of the highly conserved arginine residue at the 376 position to histidine p.(Arg376His). The following criteria was used in classifying this variant: This variant localizes to coding exon 9 of the SCN5A gene (27 exons in total;NM_001160161.2). Functional studies of the variant showed reduction of the inward sodium current in cells expressing the p.Arg376His variant compared with the wildtype, which is consistent with a Brugada syndrome pattern (PMID: 24295898). This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (2/247,596, 0 homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in the literature segregating with disease in one family affected with Brugada syndrome/conduction disease (PMID: 15851228), in several individuals affected with Brugada syndrome (PMID: 16344400, 28341781), in individuals referred for Brugada genetic testing (PMID: 20129283), atrial fibrillation (PMID: 18378609), hypertrophic cardiomyopathy (PMID: 27930701), in individuals referred for Brugada genetic testing (PMID: 20129283), and in individuals who suffered sudden unexplained death (PMID: 25194972, 23671135).
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058396	SCV000089916	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:15851228;PMID:16344400;PMID:20129283;PMID:18378609). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.