Submissions for variant NM_001165963.4(SCN1A):c.2791C>T (p.Arg931Cys)

dbSNP: rs121918788

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000188897	SCV000203506	likely pathogenic	not provided	2014-04-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000188897	SCV000242527	pathogenic	not provided	2017-02-01	criteria provided, single submitter	clinical testing	The Arg931Cys missense variant in the SCN1A gene has been reported as a de novo variant in multiple patients with Dravet syndrome and other SCN1A-related disorders (Ohmori et al., 2002; Depienne et al., 2009; an external mutation database). This amino acid substitution is non-conservative, as a positively charged Arginine residue is replaced by an uncharged Cysteine residue, and the gain of a Cysteine could affect disulfide bond formation in the protein. Arg931Cys alters a highly conserved position in the pore loop between the S5 and S6 segments of the second transmembrane domain, and many other variants have been reported in this region of the protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636409	SCV000757848	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-08-14	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 931 of the SCN1A protein (p.Arg931Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 12083760, 18076640). In at least one individual the variant was observed to be de novo. This variant is also known as Arg921Cys. ClinVar contains an entry for this variant (Variation ID: 68598). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. This variant disrupts the p.Arg931 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25243660, 27231140, 28079314). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000188897	SCV001248481	pathogenic	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000059475	SCV001426157	pathogenic	Severe myoclonic epilepsy in infancy	2018-07-25	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059475	SCV000091000	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004542733	SCV004785642	pathogenic	SCN1A-related disorder	2023-11-27	no assertion criteria provided	clinical testing	The SCN1A c.2791C>T variant is predicted to result in the amino acid substitution p.Arg931Cys. This variant has been reported, with many de novo occurrences, in multiple individuals with SCN1A-related disorders (Ohmori et al. 2002. PubMed ID: 12083760; Truty R et al. 2019. PubMed ID: 31440721; Gertler TS et al. 2019. PubMed ID: 31864146; Gall K et al. 2021. PubMed ID: 34469436; Jiang T et al. 2021. PubMed ID: 34489640; Chen C et al. 2022. PubMed ID: 35571373; Wyers et al. 2021. PubMed ID: 3344514). Alternate nucleotide changes affecting the same amino acid (p.Arg931Ser, p.Arg931His, p.Arg931Pro) have been reported in individuals with SCN1A-related disease and reported to be pathogenic (Do TT et al. 2017. PubMed ID: 28079314). The c.2791C>T (p.Arg931Cys) variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic.