Submissions for variant NM_001165963.4(SCN1A):c.2875T>C (p.Cys959Arg)

dbSNP: rs121918796

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001387943	SCV001588710	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2020-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with arginine at codon 959 of the SCN1A protein (p.Cys959Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Dravet syndrome (PMID: 12754708). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68607). 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.
Lifecell International Pvt. Ltd	RCV000059484	SCV001754810	likely pathogenic	Severe myoclonic epilepsy in infancy		criteria provided, single submitter	clinical testing	A heterozygous missense variant (c.2875T>C) in exon 18 of the SCN1A gene that results in the amino acid substitution from cysteine to arginine at codon 959 (p.Cys959Arg) was identified. This variant is not reported in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by SIFT and PolyPhen2 is damaging. The observed variant has previously been reported in patients affected with severe myoclonic epilepsy of infancy (Claes L, et al., 2003). The variant was added to dbSNP as rs121918796 in version 133. This variant was found in ClinVar (Variant 68607) with a classification of Not Provided and a review status of (0 stars) no assertion provided. The Missense Variants Z- Score for this variant is 5.23. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). The Missense Badness and MPC scores for this variant is 1.00 and 3.60 respectively. Missense Badness Score is the normalized fold difference of missense substitutions between observed and expected variants from ExAC dataset. This score is then combined with orthogonal deleteriousness metrics into one score called MPC (for Missense badness, PolyPhen-2, and Constraint) designed to classify whether a missense variants is deleterious. Variants with MPC ≥ 2 have a rate nearly 6 times higher in cases than in controls. While those with intermediate MPC values (1 ≤ MPC less than 2) have a more modest excess in cases. Based on the above evidence this variant has been classified as likely pathogenic according to the ACMG guidelines.
UniProtKB/Swiss-Prot	RCV000059484	SCV000091009	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided