Submissions for variant NM_001165963.4(SCN1A):c.2792G>A (p.Arg931His)

dbSNP: rs794726718

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Bioinformatics, Peking University	RCV000180822	SCV000221786	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
Athena Diagnostics Inc	RCV000180822	SCV000255819	pathogenic	Severe myoclonic epilepsy in infancy	2015-04-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000412755	SCV000490893	pathogenic	not provided	2017-07-06	criteria provided, single submitter	clinical testing	The R931H pathogenic variant in the SCN1A gene has been reported multiple times in association with SCN1A-related disorders (Zuberi et al., 2011; Catarino et al., 2011; Rilstone et al., 2012). It was not observed in approximately 6,500 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 R931H variant is a conservative amino acid substitution. This substitution occurs at a conserved position predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the second homologous domain. Different missense variants in the same residue (R931C, R931P) as well as multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the presence of the R931H variant is consistent with the diagnosis of a SCN1A-related disorder.
Invitae	RCV000457088	SCV000548777	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-09-07	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with Dravet syndrome (PMID: 22780858, 25243660, 27231140, 28079314). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. 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: 12083760, 18076640). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 189869). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 931 of the SCN1A protein (p.Arg931His).
Fulgent Genetics, Fulgent Genetics	RCV000763459	SCV000894236	pathogenic	Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV002281565	SCV002570035	pathogenic	Migraine, familial hemiplegic, 3	2002-09-08	no assertion criteria provided	research