ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4786C>T (p.Arg1596Cys)

dbSNP: rs121917993
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188978 SCV000242609 pathogenic not provided 2022-05-27 criteria provided, single submitter clinical testing Published functional studies demonstrate loss of function (Kluckova et al., 2020); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the intracellular loop between S2 and S3 of the fourth homologous domain; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18930999, 28202706, 29144225, 27781031, 31009440, 23527921, 17903680, 17347258, 24328833, 32238909, 32538476, 26188943, 32090326, 32086284, 27465585, 34226156, 21248271, 33841294, 32581296)
Athena Diagnostics Inc RCV000188978 SCV000615039 pathogenic not provided 2016-09-29 criteria provided, single submitter clinical testing
Invitae RCV000794558 SCV000933973 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2021-11-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1596 of the SCN1A protein (p.Arg1596Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe epilepsy (PMID: 17347258, 17903680, 26188943, 27781031). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68553). 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. This variant disrupts the p.Arg1596 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21248271, 26188943). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Cavalleri Lab, Royal College of Surgeons in Ireland RCV001031013 SCV001160806 likely pathogenic Generalized epilepsy with febrile seizures plus, type 2 2019-12-11 criteria provided, single submitter research ACMG evidence PS2, PP2, PP3
CeGaT Center for Human Genetics Tuebingen RCV000188978 SCV001245868 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001253159 SCV001428734 pathogenic Severe myoclonic epilepsy in infancy 2020-02-26 criteria provided, single submitter clinical testing This variant was identified as de novo (maternity and paternity confirmed).
Institute of Human Genetics, University of Leipzig Medical Center RCV001031013 SCV002526731 pathogenic Generalized epilepsy with febrile seizures plus, type 2 2022-05-31 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PS4, PM1, PM5, PM2_SUP, PP2, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265592 SCV002548154 pathogenic Autosomal dominant epilepsy 2022-05-30 criteria provided, single submitter clinical testing Variant summary: SCN1A c.4786C>T (p.Arg1596Cys) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250168 control chromosomes. c.4786C>T has been reported in the literature in multiple individuals affected with SCN1A-Related Seizure Disorder (example, Depienne_2008, Harkin_2007, Claes_2009, Diugos_2007, Kim_2014). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
UniProtKB/Swiss-Prot RCV000059427 SCV000090951 not provided Focal epilepsy no assertion provided not provided
PerkinElmer Genomics RCV000188978 SCV002020003 pathogenic not provided 2020-02-28 no assertion criteria provided clinical testing

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