ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.3734G>A (p.Arg1245Gln)

gnomAD frequency: 0.00001  dbSNP: rs121917912
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188926 SCV000242556 likely pathogenic not provided 2024-04-02 criteria provided, single submitter clinical testing Identified in multiple patients with Dravet syndrome or other SCN1A-related epilepsy referred for genetic testing at GeneDx and in published literature (PMID: 28202706, 21906962, 36993157); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the extracellular loop between the S1 and S2 transmembrane segments of the third homologous domain; This variant is associated with the following publications: (PMID: 18804930, 21906962, 17054684, 24331359, 32347949, 24136861, 17381446, 31440721, 36993157, 35074891, 28202706)
Labcorp Genetics (formerly Invitae), Labcorp RCV000636387 SCV000757826 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2024-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1245 of the SCN1A protein (p.Arg1245Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant severe myoclonic epilepsy of infancy (PMID: 17054684, 21906962, 28202706). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68533). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
New York Genome Center RCV001836729 SCV002097866 likely pathogenic Generalized epilepsy with febrile seizures plus, type 2 2021-01-29 criteria provided, single submitter clinical testing The inherited c.3734G>A (p.Arg1245Gln) variant identified in the SCN1A gene substitutes a very well conserved Arginine for Glutamine at amino acid 1245/2010(exon 22/29). This variant is found with low frequency in gnomAD(v3.0) (1 heterozygote, 0 homozygotes; allele frequency: 6.62e-6) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.001) and Pathogenic (REVEL; score: 0.808) to the function of the canonical transcript. This variant is reported as Pathogenic / Likely Pathogenic in ClinVar (VarID: 68533). The c.3734G>A (p.Arg1245Gln) variant identified here has been previously reported in several individuals in the literature with SCN1A associated epilepsy syndromes [PMID:17054684; PMID: 21906962; PMID: 28202706]. Given its low frequency in population databases, observation in several affected individuals in the literature, and in silico predictions of pathogenicity, the inherited c.3734G>A (p.Arg1245Gln) variant identified in the SCN1A gene is reported as Likely Pathogenic.
MGZ Medical Genetics Center RCV001836729 SCV002581817 likely pathogenic Generalized epilepsy with febrile seizures plus, type 2 2022-08-19 criteria provided, single submitter clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc RCV004796002 SCV005416598 likely pathogenic Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2; Developmental and epileptic encephalopathy 6B criteria provided, single submitter clinical testing PP3_Moderate+PM2_Supporting+PP2+PS4_Moderate+PM6_Supporting
UniProtKB/Swiss-Prot RCV000059406 SCV000090930 not provided Severe myoclonic epilepsy in infancy no assertion provided not provided

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