Submissions for variant NM_001165963.4(SCN1A):c.5222G>A (p.Cys1741Tyr)

dbSNP: rs794726763

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Bioinformatics, Peking University	RCV000180878	SCV000221847	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
GeneDx	RCV000188996	SCV000242627	pathogenic	not provided	2013-05-03	criteria provided, single submitter	clinical testing	p.Cys1741Tyr (TGT>TAT): c.5222 G>A in exon 26 of the SCN1A gene (NM_001165963.1). The Cys1741Tyr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although Cysteine and Tyrosine are both uncharged, polar amino acids, the loss of Cysteine residue may affected disulfide bond formation in the protein. Cys1741Tyr alters a highly conserved position in the pore loop between the S5 and S6 segments of the fourth transmembrane domain, and a different missense substitution at the same position (Cys1741Arg) was reported as a de novo mutation in a patient with Dravet syndrome (Wang et al., 2012). Additionally, multiple in silico algorithms predict Cys1741Tyr is damaging to protein structure/function. Therefore, Cys1741Tyr is considered a disease-causing mutation. The variant is found in EPILEPSY panel(s).
Invitae	RCV002516537	SCV003524717	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys1741 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23934111). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 189926). This missense change has been observed in individual(s) with clinical features of SCN1A-related conditions and/or Dravet syndrome (PMID: 26096185, 29655203). 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 cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1741 of the SCN1A protein (p.Cys1741Tyr).