Submissions for variant NM_001165963.4(SCN1A):c.1177C>T (p.Arg393Cys)

dbSNP: rs121917929

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000188854	SCV000233030	pathogenic	not provided	2014-09-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000188854	SCV000242484	pathogenic	not provided	2020-10-05	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17347258, 29186148, 17054684, 18930999, 24502503, 17561957, 23934111, 21868258, 32090326)
Invitae	RCV000554304	SCV000633810	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-10-13	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 393 of the SCN1A protein (p.Arg393Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 17054684, 18930999, 21868258, 22848613, 23934111). In at least one individual the variant was observed to be de novo. This variant is also known as 2:166903480G>A. ClinVar contains an entry for this variant (Variation ID: 68505). 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. For these reasons, this variant has been classified as Pathogenic.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000857236	SCV000999823	pathogenic	Seizure; Intellectual disability, mild	2018-08-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000059377	SCV001136059	pathogenic	Severe myoclonic epilepsy in infancy	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000188854	SCV001249703	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Suma Genomics	RCV002262611	SCV002543784	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
3billion	RCV000059377	SCV002573275	pathogenic	Severe myoclonic epilepsy in infancy	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068505). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 17054684). Different missense changes at the same codon (p.Arg393His, p.Arg393Pro, p.Arg393Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068504 , VCV000068506 , VCV000530476). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Mayo Clinic Laboratories, Mayo Clinic	RCV000188854	SCV004225969	pathogenic	not provided	2022-03-11	criteria provided, single submitter	clinical testing	PP3, PM1, PM2, PM5, PM6, PS2, PS4_moderate
UniProtKB/Swiss-Prot	RCV000059377	SCV000090901	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided