ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.2678G>A (p.Arg893His) (rs199473172)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766747 SCV000617274 uncertain significance not provided 2017-09-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The R893H variant has been reported in three individuals referred for Brugada syndrome testing; however, specific clinical and family history information was not provided (Kapplinger et al., 2010). Additionally, the R893H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. While a missense variant in the same residue (R893C) has been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), the pathogenicity of this variant has not been definitively determined. Nonetheless, the R893H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Finally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000520411 SCV000747932 uncertain significance not specified 2016-06-28 criteria provided, single submitter clinical testing
Invitae RCV000058518 SCV000832454 pathogenic Brugada syndrome 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 893 of the SCN5A protein (p.Arg893His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Brugada syndrome (PMID: 28341781, 23503384, Invitae). This variant has also been reported in individuals referred for Brugada syndrome testing, an individual with sudden death, and in asymptomatic relatives of an individual with sudden unexplained death (PMID: 20129283, 29247119, 20381179). ClinVar contains an entry for this variant (Variation ID: 67749). Experimental studies have shown that this missense change produces an abnormal electrophysiological effect in transfected HEK-293 cells (PMID: 25904541). This variant disrupts the p.Arg893 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28341781, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058518 SCV000090038 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). 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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