ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5648C>T (p.Pro1883Leu) (rs755162776)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520769 SCV000616919 uncertain significance not provided 2017-09-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The P1884L variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 10/16512 (0.06%) alleles from individuals of South Asian ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). The P1884L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000812516 SCV000952832 uncertain significance Brugada syndrome 2018-07-27 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1884 of the SCN5A protein (p.Pro1884Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs755162776, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 449118). 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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