Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000413989 | SCV000491702 | pathogenic | not provided | 2016-11-14 | criteria provided, single submitter | clinical testing | The confirmed de novo C345F variant in the SCN1A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server) It is a non-conservative amino acid substitution that alters a conserved position in the predicted pore forming loop between the S5 and S6 transmembrane segments of the first homologous domain. A different missense substitution at the same position (C345R) has published as an assumed de novo variant in a patient with Dravet syndrome (Depienne et al., 2009), supporting the functional importance of this position in the protein. In silico analysis predicts the C345F variant is probably damaging to the protein structure/function. Therefore, we interpret C345F as a pathogenic variant. |
| Labcorp Genetics |
RCV005090671 | SCV005733472 | likely pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2024-07-26 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 345 of the SCN1A protein (p.Cys345Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 373136). 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 SCN1A protein function with a positive predictive value of 95%. This variant disrupts the p.Cys345 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18930999). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |