ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5690G>A (p.Arg1897His) (rs370694515)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000247589 SCV000320364 uncertain significance Cardiovascular phenotype 2015-10-21 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,Insufficient or conflicting evidence
Baylor-Hopkins Center for Mendelian Genomics,Johns Hopkins University RCV000466757 SCV000541075 pathogenic Arrhythmogenic right ventricular dysplasia/cardiomyopathy criteria provided, single submitter research
GeneDx RCV000767135 SCV000589399 uncertain significance not provided 2018-03-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The R1898H variant has been reported in one patient with DCM (Haas et al., 2015) and in one patient with clinical features suggestive of arrhythmogenic right ventricular cardiomyopathy (ARVC) (Te Riele et al., 2017). The R1898H variant is observed in 7/30782 (0.02%) alleles from individuals of South Asian ancestry in large population cohorts (Lek et al., 2016). The R1898H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000234809 SCV000240229 pathogenic Long QT syndrome 3 2014-01-01 criteria provided, single submitter research
Invitae RCV000797409 SCV000936963 uncertain significance Brugada syndrome 2018-07-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1898 of the SCN5A protein (p.Arg1898His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs370694515, ExAC 0.02%). This variant has been reported in the literature in an individual affected with dilated cardiomyopathy (PMID: 25163546), and individual with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705), and in healthy controls (PMID: 25904541). ClinVar contains an entry for this variant (Variation ID: 207974). Experimental studies have shown that this missense change decreases SCN5A channel density but not cluster size or steady-stage voltage dependence of inactivation (PMID: 28069705). The clinical significance of these results is unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000216249 SCV000272417 uncertain significance not specified 2015-02-02 criteria provided, single submitter clinical testing The p.Arg1898His variant in SCN5A has not been previously reported in individual s with cardiomyopathy, but has been identified in 4/16512 South Asian chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs370694515). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1898His variant is uncertain.

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