Submissions for variant NM_000334.4(SCN4A):c.4342C>T (p.Arg1448Cys)

dbSNP: rs121908544

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255921	SCV000322222	pathogenic	not provided	2021-09-20	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in multiple unrelated families with paramyotonia congenita (Ptacek et al., 1992; Meyer-Kleine et al., 1994); Functional studies indicated that R1448C impacts the channel inactivation in vitro (Chahine et al., 1994; Yang et al., 1994); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16801039, 8005599, 18166706, 21490317, 26036855, 23417379, 27199537, 12483017, 12552059, 7809121, 30028520, 30930557, 31544778, 32849172, 26484179, 20301669, 32660787, 1316765, 8110459)
Eurofins Ntd Llc (ga)	RCV000255921	SCV000340609	pathogenic	not provided	2016-04-06	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000255921	SCV000615098	pathogenic	not provided	2023-06-16	criteria provided, single submitter	clinical testing	This variant has been identified in multiple individuals with paramyotonia congenita and has been shown to associate with paramyotonia congenita in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Cells expressing this variant showed slower current inactivation, faster recovery from inactivation and increased persistent current when compared to WT (PMID: 7809121, 8833340, 21317558). The variant is located in a region that is considered important for protein function and/or structure.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206951	SCV000658579	pathogenic	Familial hyperkalemic periodic paralysis	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1448 of the SCN4A protein (p.Arg1448Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paramyotonia congenita (PMID: 1316765, 8005599, 16801039). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5898). 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%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7809121, 8110459, 21490317). This variant disrupts the p.Arg1448 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1316765, 8005599, 8110459). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
DASA	RCV001813736	SCV002061166	pathogenic	Hypokalemic periodic paralysis, type 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.4342C>T;p.(Arg1448Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 5898; PMID: 12483017; 12552059; 16801039; 18033047; 21490317; 26484179; 27199537; 26036855; 30028520) - PS4.This variant is not present in population databases (rs121908544, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID: 5899; 221263; 221262) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 12483017; 16801039; 18033047; 26484179) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000255921	SCV002563427	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	SCN4A: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3, PP4
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV003989102	SCV004805662	pathogenic	Hypokalemic periodic paralysis, type 2	2024-04-01	criteria provided, single submitter	clinical testing	A heterozygous missense variant in exon 24 of the SCN4A gene that results in the amino acid substitution of Cysteine for Arginine at codon 1448 (p.Arg1448Cys) was detected. The observed variant has previously been reported in patients in affected with SCN4A related conditions [PMID:16801039]. The variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico prediction of the variant are damaging by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
OMIM	RCV000006258	SCV000026440	pathogenic	Paramyotonia congenita of Von Eulenburg	1992-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000206951	SCV000262571	not provided	Familial hyperkalemic periodic paralysis		no assertion provided	literature only