ClinVar Miner

Submissions for variant NM_001330260.2(SCN8A):c.3955G>T (p.Ala1319Ser)

dbSNP: rs796053214
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189275 SCV000242907 pathogenic not provided 2013-12-04 criteria provided, single submitter clinical testing p.Ala1319Ser (GCC>TCC): c.3955 G>T in exon 22 of the SCN8A gene (NM_014191.3).The Ala1319Ser 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 non-conservative amino acid substitution of a non-polar Alanine residue with a polar Serine residue. This variant occurs at a highly conserved position between the S4 and S5 segments in the third transmembrane domain of the SCN8A protein and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge, other missense mutations in the same region of the protein have not been reported in association with epilepsy. This variant has been observed de novo without verified parentage. The variant is found in INFANT-EPI panel(s).
Invitae RCV000700845 SCV000829620 likely pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-04-09 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of SCN8A-related conditions (PMID: 29655203, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207117). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 1319 of the SCN8A protein (p.Ala1319Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine.

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.