Submissions for variant NM_001330260.2(SCN8A):c.4949C>T (p.Ala1650Val)

dbSNP: rs796053224

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189285	SCV000242917	pathogenic	not provided	2013-10-18	criteria provided, single submitter	clinical testing	p.Ala1650Val (GCC>GTC): c.4949 C>T in exon 27 of the SCN8A gene (NM_014191.3). The Ala1650Val 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. This variant is a conservative substitution of one uncharged, non-polar amino acid for another. It alters a highly conserved position between the S4 and S5 subunits of the forth transmembrane domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. This variant has been observed de novo without verified parentage. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089956	SCV005815720	likely pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-07-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1650 of the SCN8A protein (p.Ala1650Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SCN8A-related conditions (PMID: 31904124). ClinVar contains an entry for this variant (Variation ID: 207127). 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%. This variant disrupts the p.Ala1650 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24888894, 29655203, 30171078, 32090326). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.