Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000493100 | SCV000582796 | uncertain significance | not provided | 2017-05-16 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the SCN8A gene. The V1560M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V1560M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V1560M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species and is predicted to be within the transmembrane segment S2 of the fourth homologous domain. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with SCN8A-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
Invitae | RCV001349506 | SCV001543857 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2023-11-24 | 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 1560 of the SCN8A protein (p.Val1560Met). This variant is present in population databases (rs764328953, gnomAD 0.009%). 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: 430073). 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%. 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. |