ClinVar Miner

Submissions for variant NM_001330260.2(SCN8A):c.1349C>T (p.Ala450Val)

gnomAD frequency: 0.00002  dbSNP: rs755154133
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 RCV000658199 SCV000779970 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN8A gene. The A450V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A450V variant is observed in 1/3492 (0.03%) allele from individuals of Finnish background in large population cohorts (Lek et al., 2016). The A450V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV003588660 SCV004290983 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2023-11-01 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 450 of the SCN8A protein (p.Ala450Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 546338). 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 with a negative predictive value of 95%. 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.

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.