ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2398C>T (p.Arg800Cys) (rs764252430)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521255 SCV000617057 uncertain significance not provided 2018-09-04 criteria provided, single submitter clinical testing A novel R800C variant of uncertain significance was identified in the SCN5A gene. Although R800C has not been published as a pathogenic variant or as a benign variant to our knowledge, a different missense variant affecting this same residue (R800L) has been reported in association with LQTS in one family who also harbored a variant in the SNTA1 gene (Hu et al., 2013). In addition, missense variants in nearby residues (V789I, R808C, R808P) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014); however, the full significance of these variants is unknown. The R800C variant was not observed in approximately 6,400 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The R800C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammalian species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge no studies have been performed to determine the functional effect of the R800C variant.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000701968 SCV000830795 uncertain significance Brugada syndrome 2018-05-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 800 of the SCN5A protein (p.Arg800Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs764252430, ExAC 0.006%). This variant has not been reported in the literature in individuals with SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 449205). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.

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