ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1127G>A (p.Arg376His) (rs199473101)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617435 SCV000737601 likely pathogenic Cardiovascular phenotype 2018-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
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.
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.
Invitae RCV000058396 SCV000760186 pathogenic Brugada syndrome 2018-01-31 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.

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