ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5293A>G (p.Met1765Val) (rs199473310)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000559094 SCV000637177 uncertain significance Brugada syndrome 2017-05-10 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1766 of the SCN5A protein (p.Met1766Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with long QT syndrome (PMID: 23174487), though it is unclear whether they are unrelated or from the same family. This variant identified in the SCN5A gene is located in the transmembrane DIV-S6 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). A different missense substitution at this codon (p.Met1766Leu) has been determined to be pathogenic (PMID: 12123767). This suggests that the methionine residue is critical for SCN5A protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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