ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.1127G>A (p.Arg376His) (rs199473101)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182960 SCV000235357 pathogenic not provided 2018-06-06 criteria provided, single submitter clinical testing The R376H variant in the SCN5A gene has been reported in association with Brugada syndrome and cardiac conduction disease, including one individual with right ventricular fatty infiltrate (Rossenbacker T et al., 2004; Frustaci A et al., 2005; Darbar D et al., 2008; Kapplinger J et al., 2010). The R376H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R376H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved in mammals. Functional studies showed a significant reduction of the inward sodium current in cells that were expressing the R376H allele (Detta et al., 2014). In addition, a different missense variant at the same residue, R376C, was identified in three members of a family with sick sinus syndrome (Detta et al., 2014), supporting the functional importance of this region of the protein. Based on the ACMG recommendations, R376H is interpreted as a known pathogenic sequence change.
Ambry Genetics RCV000617435 SCV000737601 likely pathogenic Cardiovascular phenotype 2018-03-16 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, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000058396 SCV000760186 pathogenic Brugada syndrome 2020-09-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 376 of the SCN5A protein (p.Arg376His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in the literature segregating with disease in one family (PMID: 15851228), in several individuals affected with Brugada syndrome (PMID: 16344400, 28341781), 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). ClinVar contains an entry for this variant (Variation ID: 67639). Experimental studies have shown that this missense change causes a reduction of the current density consistent with a Brugada syndrome pattern (PMID: 15851228, 24295898, 21840964). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV001191913 SCV001359848 likely pathogenic Arrhythmia 2019-06-06 criteria provided, single submitter clinical testing
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.

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