Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000687774 | SCV000815360 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2021-08-30 | 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: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 567631). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 1145 of the SCN8A protein (p.Glu1145Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. |
| New York Genome Center | RCV001281508 | SCV001468817 | uncertain significance | Seizure | 2019-06-21 | criteria provided, single submitter | clinical testing | The inherited c.3433G>A (p.Glu1145Lys) variant identified in the SCN8A gene substitutes a highly conserved Glutamic Acid for Lysine at amino acid 1145/1981 (coding exon 18/26). It is found with low frequency in gnomAD (1 heterozygous individual, no homozygous individuals; allele frequency:4.161e-6), and is absent in ExAC, suggesting it is not a common benign variant in the populations represented in these databases. In silico algorithms predict that this variant is deleterious (Provean; score: -2.62) and damaging (SIFT; score: 0.004) to the function of the canonical transcript. This variant is reported in ClinVar as a Variant of Uncertain Significance (VarID: 567631), and to our current knowledge has not been reported in affected individuals in the literature. The Glu1145 residue is within cytoplasmic loop2, and while not a hot spot of pathogenic variants in SCN8A, other clinically significant variants have been identified within this genomic region [https://www.ncbi.nlm.nih.gov/books/NBK379665, PMID: 26029160]. Given the lack of compelling information regarding the pathogenicity of the inherited c.3433G>A (p.Glu1145Lys) variant it is reported here as a Varaint of Uncertain Significance. |