Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000189275 | SCV000242907 | pathogenic | not provided | 2013-12-04 | criteria provided, single submitter | clinical testing | p.Ala1319Ser (GCC>TCC): c.3955 G>T in exon 22 of the SCN8A gene (NM_014191.3).The Ala1319Ser missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Serine residue. This variant occurs at a highly conserved position between the S4 and S5 segments in the third transmembrane domain of the SCN8A protein and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge, other missense mutations in the same region of the protein have not been reported in association with epilepsy. This variant has been observed de novo without verified parentage. The variant is found in INFANT-EPI panel(s). |
Invitae | RCV000700845 | SCV000829620 | likely pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2020-04-09 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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"). This variant has been observed in individual(s) with clinical features of SCN8A-related conditions (PMID: 29655203, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207117). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 1319 of the SCN8A protein (p.Ala1319Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. |