ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.1277A>G (p.Tyr426Cys) (rs796052973)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.