ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1051G>A (p.Gly351Ser) (rs201276017)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000772074 SCV000905103 uncertain significance Arrhythmia 2018-07-24 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain DI of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with juvenile myoclonic epilepsy and long QT syndrome (Ho 2016). This variant has also been identified in 3/246036 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000458589 SCV000545027 uncertain significance Brugada syndrome 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 351 of the SCN5A protein (p.Gly351Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs201276017, ExAC 0.002%) but has not been reported in the literature in individuals with a SCN5A-related disease. 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. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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