Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000489736 | SCV000576699 | uncertain significance | not provided | 2017-04-21 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the SCN8A gene. The M1313I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M1313I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a conserved position predicted to be within the intracellular loop between S4 and S5 transmembrane segments of the third homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the M1313I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
Invitae | RCV001865509 | SCV002272619 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2022-12-06 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 426295). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1313 of the SCN8A protein (p.Met1313Ile). |