Submissions for variant NM_001165963.4(SCN1A):c.2836C>T (p.Arg946Cys)

dbSNP: rs121918775

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000118240	SCV000152602	pathogenic	Generalized epilepsy with febrile seizures plus, type 2	2013-11-26	criteria provided, single submitter	clinical testing
Center for Bioinformatics, Peking University	RCV000059481	SCV000221901	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
GeneDx	RCV000189085	SCV000242716	pathogenic	not provided	2022-11-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, as R946C leads to a complete loss of sodium ion channel function (Volkers et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the second homologous domain; This variant is associated with the following publications: (PMID: 24168886, 18804930, 16458823, 23195492, 15277629, 15508916, 21248271, 30368457, 30805006, 21864321, 26096185, 19585586, 23884151, 27781031, 30868114, 30525188, 31864146, 32090326, 29573403, 33903184, 35663268, Bosselmann2022[computational], 35231114, 14738421)
Athena Diagnostics Inc	RCV000059481	SCV000255820	pathogenic	Severe myoclonic epilepsy in infancy	2015-04-15	criteria provided, single submitter	clinical testing
Invitae	RCV000636276	SCV000757715	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-03-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg946 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21371021, 21864321, 23195492, 27781031). 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 SCN1A function (PMID: 21864321). 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 SCN1A protein function. ClinVar contains an entry for this variant (Variation ID: 68604). This variant is also known as R936C. This missense change has been observed in individual(s) with Dravet syndrome (PMID: 14738421, 21864321, 23195492). In at least one individual the variant was observed to be de novo. 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 946 of the SCN1A protein (p.Arg946Cys).
CeGaT Center for Human Genetics Tuebingen	RCV000189085	SCV001248479	pathogenic	not provided	2019-03-01	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059481	SCV000091006	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000189085	SCV001739774	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000189085	SCV001957267	pathogenic	not provided		no assertion criteria provided	clinical testing