ClinVar Miner

Submissions for variant NM_006514.3(SCN10A):c.1788G>T (p.Leu596Phe) (rs764965507)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521065 SCV000620233 uncertain significance not provided 2017-08-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN10A gene. The L596F variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, although this substitution occurs at a position that is conserved across species, L596F is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000696333 SCV000824890 uncertain significance Brugada syndrome 2018-06-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 596 of the SCN10A protein (p.Leu596Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs764965507, ExAC 0.009%). This variant has not been reported in the literature in individuals with SCN10A-related disease. ClinVar contains an entry for this variant (Variation ID: 451515). 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"; Align-GVGD: "Class C0"). 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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