Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000189273 | SCV000242905 | uncertain significance | not provided | 2017-11-01 | criteria provided, single submitter | clinical testing | p.Tyr1241Cys (TAT>TGT): c.3722 A>G in exon 20 of the SCN8A gene (NM_014191.3). The Tyr1241Cys missense change in the SCN8A gene 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. The Tyr1241Cys variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size, and/or other properties and is more likely to impact the secondary structure of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. It alters a conserved position in the S2 transmembrane domain of the third homologous repeat; however, missense mutations associated with epilepsy have not been reported in this region of the gene. Therefore, based on the currently available information, it is unclear whether Tyr1241Cys is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). |
| Invitae | RCV003753107 | SCV004395647 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2023-06-05 | 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: 207115). This missense change has been observed in individual(s) with SCN8A-related conditions (PMID: 30968951). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1241 of the SCN8A protein (p.Tyr1241Cys). |