Submissions for variant NM_000334.4(SCN4A):c.4442C>A (p.Ala1481Asp)

dbSNP: rs763893717

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698645	SCV000827325	pathogenic	Hyperkalemic periodic paralysis	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1481 of the SCN4A protein (p.Ala1481Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SCN4A-related conditions (PMID: 17212350; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 576206). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002267623	SCV002549800	likely pathogenic	SCN4A-related non-dystrophic myotonia	2022-04-06	no assertion criteria provided	research