ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.2792G>A (p.Arg931His) (rs794726718)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
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 2017-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 931 of the SCN1A protein (p.Arg931His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Dravet syndrome (PMID: 22780858, 27231140, 28079314), including at least one de novo observation (PMID: 25243660). ClinVar contains an entry for this variant (Variation ID: 68598). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant identified in the SCN1A gene is located in the extracellular D2-P2 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. A different missense substitution at this codon (p.Arg931Cys) has been determined to be pathogenic (PMID: 12083760, 18076640). This suggests that the arginine residue is critical for SCN1A protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763459 SCV000894236 pathogenic Familial hemiplegic migraine type 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2018-10-31 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.