ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.2143G>A (p.Ala715Thr)

dbSNP: rs749400108
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001904650 SCV002124756 pathogenic Familial hyperkalemic periodic paralysis 2023-10-13 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 715 of the SCN4A protein (p.Ala715Thr). This variant is present in population databases (rs749400108, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of autosomal dominant paramyotonia congenita (PMID: 16786525, 33965302; Invitae). ClinVar contains an entry for this variant (Variation ID: 1359989). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN4A protein function. This variant disrupts the p.Ala715 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been observed in individuals with SCN4A-related conditions (PMID: 22094069; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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