Submissions for variant NM_000334.4(SCN4A):c.2078T>C (p.Ile693Thr)

dbSNP: rs80338956

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485864	SCV000567467	pathogenic	not provided	2017-10-12	criteria provided, single submitter	clinical testing	The I693T substitution in the SCN4A gene has been reported multiple times in association with SCN4A-relateddisorders including paramyotonia congenita and hyperkalemic periodic paralysis (Song et al., 2012; Pagon etal., 1993; Matthews et al., 2008; SCN4A LOVD). The I693T variant was not observed in approximately6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The I693T variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ inpolarity, charge, size and/or other properties. This substitution alters a conserved position that is predicted tobe within the cytoplasmic loop between transmembrane segments 4 and 5 in the second homologous repeatdomain. Additionally, missense variants in the same (I693L/M) and nearby (L689I/V) residues have beenreported in the Human Gene Mutation Database in association with SCN4A-related disorders (Stenson et al.,2014). Therefore, we interpret I693T as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020266	SCV000776553	pathogenic	Familial hyperkalemic periodic paralysis	2022-11-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN4A function (PMID: 9508833). 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: 5923). This missense change has been observed in individuals with hyperkalemic periodic paralysis and/or paramyotonia congenita (PMID: 2649440, 8902732, 19015492, 20076800, 22926674). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 693 of the SCN4A protein (p.Ile693Thr).
Athena Diagnostics	RCV000485864	SCV000843661	pathogenic	not provided	2018-01-09	criteria provided, single submitter	clinical testing
OMIM	RCV000006286	SCV000026468	pathogenic	Paramyotonia congenita of Von Eulenburg	2008-11-18	no assertion criteria provided	literature only
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002267605	SCV002549807	pathogenic	SCN4A-related non-dystrophic myotonia	2022-04-06	no assertion criteria provided	research