ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2657A>G (p.His886Arg)

dbSNP: rs199473169
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003656269 SCV001212934 uncertain significance not provided 2019-12-18 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals with SCN5A-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with arginine at codon 886 of the SCN5A protein (p.His886Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine.
PreventionGenetics, part of Exact Sciences RCV003396662 SCV004110287 uncertain significance SCN5A-related condition 2023-03-26 criteria provided, single submitter clinical testing The SCN5A c.2657A>G variant is predicted to result in the amino acid substitution p.His886Arg. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Different nucleotide substitutions affecting the same amino acid (p.His886Pro and p.His886Gln) have been reported in individuals with Brugada syndrome (Kapplinger et al. 2010. PubMed ID: 20129283; Robyns et al. 2018. PubMed ID: 29709101). Although we suspect that the c.2657A>G (p.His886Arg) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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