Submissions for variant NM_001165963.4(SCN1A):c.4942C>T (p.Arg1648Cys)

dbSNP: rs121918791

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000059520	SCV000255832	pathogenic	Severe myoclonic epilepsy in infancy	2014-11-25	criteria provided, single submitter	clinical testing
GeneDx	RCV003233101	SCV003931061	pathogenic	not provided	2022-12-06	criteria provided, single submitter	clinical testing	Observed in multiple unrelated patients with infantile-onset epilepsy referred for genetic testing at GeneDx and in published literature (Ohmori et al., 2002); Published functional studies demonstrate a damaging effect as this variant alters the closing and extended opening of sodium channels, impairing normal channel function and subsequent neuron firing (Rhodes et al., 2004; Thompson et al., 2012); Additional functional studies in a drosophila model demonstrate that R1648C exhibits spontaneous and temperature-sensitive seizure activity, recapitulating the disease state (Roemmich et al., 2021); Missense variants in this gene are often considered pathogenic (HGMD); 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 variant is associated with the following publications: (PMID: 31069529, 11567038, 25378155, 10742094, 31625145, Nisevic_2015_Review, 33236643, 30735520, 20735403, Giunti_2019_Abstract, 31782251, 31879226, 17054685, 32581296, 30038559, 22701429, 26544041, 15263074, 23086956, 18275929, 29573403, 32090326, 12083760, 34475263)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003588572	SCV004292115	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-09-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1648 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10742094, 20522430). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SCN1A function (PMID: 15263074, 23086956). 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. ClinVar contains an entry for this variant (Variation ID: 68641). This variant is also known as C4912T (p.R1638C). This missense change has been observed in individual(s) with severe myoclonic epilepsy in infancy (PMID: 12083760). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1648 of the SCN1A protein (p.Arg1648Cys).
UniProtKB/Swiss-Prot	RCV000059520	SCV000091051	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided
Channelopathy-Associated Epilepsy Research Center	RCV000059520	SCV004809278	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	literature only