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

dbSNP: rs121917993

Total submissions: 12

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	RCV000188978	SCV000615039	pathogenic	not provided	2016-09-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000794558	SCV000933973	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-11-13	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). 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%. 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).
Revvity Omics, Revvity	RCV000188978	SCV002020003	pathogenic	not provided	2020-02-28	criteria provided, single submitter	clinical testing
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.
Department of Neurology, Zibo Changguo Hospital	RCV001031013	SCV005889670	pathogenic	Generalized epilepsy with febrile seizures plus, type 2	2025-01-09	criteria provided, single submitter	clinical testing	PS4, PM2_Supporting, PM5, PP2, PP3_Strong
UniProtKB/Swiss-Prot	RCV000059427	SCV000090951	not provided	Focal epilepsy		no assertion provided	not provided
Channelopathy-Associated Epilepsy Research Center	RCV001253159	SCV004809276	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	literature only