ClinVar Miner

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

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Total submissions: 5
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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 2021-09-17 criteria provided, single submitter clinical testing Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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 1st homologous domain; This variant is associated with the following publications: (PMID: 33851920, 18413471, 28202706, 26096185, 19464195, 23248692, 28150151)
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.
3billion RCV001775078 SCV002012093 likely pathogenic Generalized epilepsy with febrile seizures plus, type 2 2021-10-02 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (ClinVar ID: VCV000376243.1, PS1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as likley pathogenic according to the recommendation of ACMG/AMP guideline.
UniProtKB/Swiss-Prot RCV000059374 SCV000090898 not provided Generalized epilepsy with febrile seizures plus, type 1 no assertion provided not provided

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