ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.1130G>A (p.Arg377Gln) (rs121917957)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Bioinformatics, Peking University RCV000180936 SCV000221917 pathogenic Severe myoclonic epilepsy in infancy 2014-12-20 criteria provided, single submitter research
GeneDx RCV000188861 SCV000242491 likely pathogenic not provided 2018-07-23 criteria provided, single submitter clinical testing A R377Q variant that is likely pathogenic has been identified in the SCN1A gene. The R377Q missense change has been reported previously in a child with GEFS+ and was also identified in the child's mother; however no clinical information was provided on the mother, and no functional studies have been performed (Zucca et al., 2008). The R377Q variant subsequently has been reported in a child with myoclonic jerks with focal partial seizures and was also identified in the child's mother who has a history of febrile seizures in childhood; however, no functional studies have been performed (Pratico et al., 2016). The R377Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R377Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution alters a highly conserved position predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the first homologous domain of the SCN1A protein. Multiple missense variants in nearby residues have been reported in association with SCN1A-related disorders (Stenson et al., 2014; SCN1A Variant Database), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. The variant is found in EPILEPSY panel(s).
Invitae RCV001226020 SCV001398316 likely pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-04-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 377 of the SCN1A protein (p.Arg377Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of SCN1A-related conditions (PMID: 18413471, Invitae). ClinVar contains an entry for this variant (Variation ID: 68502). 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 disrupts the p.Arg377 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 18076640), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
UniProtKB/Swiss-Prot RCV000059374 SCV000090898 not provided Generalized epilepsy with febrile seizures plus, type 1 no assertion provided not provided

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.