ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1597C>T (p.Arg533Cys)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000774304 SCV000908006 uncertain significance Arrhythmia 2018-10-27 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the linker region between transmembrane domains DI and DII 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 RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/275610 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000697228 SCV000825825 uncertain significance Brugada syndrome 2018-09-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 533 of the SCN5A protein (p.Arg533Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs775576991, ExAC 0.01%). This variant has been observed in an individual with long QT syndrome as compound heterozygous with another variant in SCN5A (PMID: 27485560). 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. 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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