Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000636268 | SCV000757707 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2022-02-28 | 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. 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"). ClinVar contains an entry for this variant (Variation ID: 530412). 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 lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1123 of the SCN8A protein (p.Lys1123Gln). |
| New York Genome Center | RCV002227484 | SCV002506796 | uncertain significance | Cognitive impairment with or without cerebellar ataxia; Developmental and epileptic encephalopathy, 13; Seizures, benign familial infantile, 5 | 2021-07-16 | criteria provided, single submitter | clinical testing | The inherited c.3367A>C (p.Lys1123Gln) variant identified in the SCN8A gene substitutes a very well conserved Lysine for Glutamine at amino acid 1123/1981 (exon 17/27). This variant is absent from gnomAD(v3.1.1), suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.013) and Pathogenic (REVEL; score:0.6389) to the function of the canonical transcript.This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:530412) and to our current knowledge has not been reported in affected individuals in the literature. The p.Lys1123 residue is within one of the cytoplasmic domains of SCN8A (UniProtKB:Q9UQD0). Given the lack of compelling evidence for its pathogenicity, the inherited c.3367A>C (p.Lys1123Gln) variant identified in the SCN8A gene is reported as a Variant of UncertainSignificance. |