Submissions for variant NM_001330260.2(SCN8A):c.760G>A (p.Val254Met)

dbSNP: rs1057518293

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414697	SCV000491803	uncertain significance	not specified	2016-11-28	criteria provided, single submitter	clinical testing	The V254M variant in the SCN8A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V254M variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the V254M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, we interpret V254M as a variant of uncertain significance.
Invitae	RCV000693932	SCV000822355	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 254 of the SCN8A protein (p.Val254Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 373224). 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 SCN8A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.