Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000796212 | SCV000935716 | pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2022-11-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val1315 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26993267, 29432985). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 642701). This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1315 of the SCN8A protein (p.Val1315Ala). |
| New York Genome Center | RCV001255042 | SCV001431133 | likely pathogenic | Seizure | 2019-11-14 | no assertion criteria provided | clinical testing | The c.3944T>C variant substitutes a completely conserved Valine for Alanine at amino acid 1315/1981 (coding exon 22/27). This variant is absent from gnomAD and ExAC, suggesting it is not a common benign variant in the populations represented in these databases. In silico algorithms predict this variant to be Deleterious (Provean; score: -3.59) and Damaging (SIFT; score: 0.003)to the function of the canonical transcript. This variant is reported in ClinVar as a variant of Uncertain Significance (VarID:642701), and while the p.Val1315Ala variant identified in this individual has not been reported in affected individuals in the literature, a different amino acid change at the same amino acid (p.Val1315Met) has been identified in 3 affected individuals, although functional studies have not been reported (Seizure. 2018 Mar;56:47-49; Epilepsia. 2019 May;60(5):845-856; J Med Genet. 2016 May;53(5):310-317). This variant was identified de novo mosaic in a patient submitted for clinical WGS testing. |