ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.826C>A (p.Leu276Ile) (rs1553705529)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000530816 SCV000637206 uncertain significance Brugada syndrome 2018-01-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 276 of the SCN5A protein (p.Leu276Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN5A-related disease. A different missense substitution at this codon (p.Leu276Gln) has been determined to be pathogenic (PMID: 17697823, 20129283, 23321620). This suggests that the leucine residue is critical for SCN5A protein function and that other missense substitutions at this position may also be pathogenic. Although 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 C0"), This variant affects a amino acid position that is conserved among other members of the sodium channel family of proteins (PMID: 22581653). In summary, this is a novel missense change that affects a residue important for protein function. However, in the absence of confirmed segregation or functional studies, at this time this change has been classified as a Variant of Uncertain Significance.

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