Submissions for variant NM_001330260.2(SCN8A):c.5597G>A (p.Arg1866Gln)

dbSNP: rs1555231108

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521968	SCV000619014	uncertain significance	not provided	2017-07-11	criteria provided, single submitter	clinical testing	The R1866Q variant in the SCN8A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1866Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1866Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. 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. We interpret R1866Q as a variant of uncertain significance
Invitae	RCV002525172	SCV003461669	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2023-07-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1866 of the SCN8A protein (p.Arg1866Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 29852413). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 450430). 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 not expected to disrupt SCN8A protein function. This variant disrupts the p.Arg1866 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been observed in individuals with SCN8A-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.