Submissions for variant NM_000334.4(SCN4A):c.2014C>T (p.Arg672Cys)

dbSNP: rs80338785

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206949	SCV000815191	pathogenic	Familial hyperkalemic periodic paralysis	2023-03-27	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with hypokalemic periodic paralysis (PMID: 15482957, 18162704, 19118277, 27199537). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg672 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10944223, 11558801, 11912116, 15557532, 18824591, 23019082, 26252573). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SCN4A function (PMID: 18824591). 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. ClinVar contains an entry for this variant (Variation ID: 21151). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 672 of the SCN4A protein (p.Arg672Cys).
Athena Diagnostics	RCV003482229	SCV004230010	pathogenic	not provided	2022-12-21	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with periodic paralysis and appears to be associated with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 18824591) The variant is located in a region that is considered important for protein function and/or structure.
Neuberg Centre For Genomic Medicine, NCGM	RCV002307367	SCV005044748	pathogenic	Hypokalemic periodic paralysis, type 2		criteria provided, single submitter	clinical testing	The missense c.2014C>T p.Arg672Cys variant in SCN4A gene has been reported in heterozygous state in multiple individuals affected with Hypokalemic periodic paralysis Weber F et al. 2018; Wang XY et al. 2015; Kim JB et al. 2007. Experimental studies have shown that this missense change affects SCN4A function Struyk AF et al. 2008. The p.Arg672Cys variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Arg672Cys in SCN4A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 672 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
GeneReviews	RCV002307367	SCV000040617	not provided	Hypokalemic periodic paralysis, type 2		no assertion provided	literature only
GeneReviews	RCV000206949	SCV000262565	not provided	Familial hyperkalemic periodic paralysis		no assertion provided	literature only