Submissions for variant NM_001165963.4(SCN1A):c.1277A>G (p.Tyr426Cys)

dbSNP: rs796052973

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188864	SCV000242494	pathogenic	not provided	2015-01-06	criteria provided, single submitter	clinical testing	p.Tyr426Cys (TAC>TGC): c.1277 A>G in exon 9 of the SCN1A gene (NM_001165963.1) The Y426C missense mutation in the SCN1A gene has been reported previously as a de novo mutation in an individual with Dravet syndrome (Depienne et al., 2009). It was also reported in two individuals with severe myoclonic epilepsy of infancy (SMEI) (Wang et al., 2012). Additionally, a different amino acid substitution at this same position (Y426N) has been reported as a de novo mutation in an individual with SMEI (Nabbout et al., 2003). The Y426C substitution alters a highly conserved position predicted to be in the in the cytoplasmic loop between the first and second homologous domains. The variant is found in INFANTV2-EPIV2-1 panel(s).
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000188864	SCV000297071	pathogenic	not provided	2015-09-02	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV001528187	SCV001739369	likely pathogenic	Severe myoclonic epilepsy in infancy		criteria provided, single submitter	clinical testing	A heterozygous missense variant (c.1277A>G) in exon 12 of the SCN1A gene that results in the amino acid substitution from tyrosine to cysteine at codon 426 (p.Tyr426Cys) was identified. There is a large physicochemical difference between tyrosine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. The Missense Variants Z-Score for this variant is 5.61.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 Score and MPC value for this variant are 0.59 and 1.92, 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 2) have a more modest excess in cases. This has been previously classified as Pathogenic in ClinVar (Variation ID 206761 as of 2020-11-05) with respect to not provided with a status of (2 stars) criteria provided, multiple submitters, no conflicts. This variant has previously been reported for Dravet syndrome by Till Á et al., 2020. The variant is present in a hot-spot region and in the Ion transport protein domain of the SCN1A protein. Based on the above evidence this variant has been classified as Likely pathogenic according to the ACMG guidelines.
Invitae	RCV001857645	SCV002125946	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-09-07	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 206761). For these reasons, this variant has been classified as Pathogenic. 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 missense change has been observed in individual(s) with Dravet syndrome (PMID: 18930999, 23195492, 30577886, 31864146). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 426 of the SCN1A protein (p.Tyr426Cys).
Athena Diagnostics Inc	RCV000188864	SCV004230000	pathogenic	not provided	2023-05-10	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene including multiple confirmed de novo occurrences. Computational tools predict that this variant is damaging.