Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000549298 | SCV000633864 | pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2023-08-10 | criteria provided, single submitter | clinical testing | This missense change has been observed in individuals with clinical features of SCN1A-related conditions (Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys1588 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17561957, 25818041). 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 461276). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1588 of the SCN1A protein (p.Cys1588Tyr). |
Gene |
RCV001796101 | SCV002032558 | likely pathogenic | not provided | 2021-11-29 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This substitution is predicted to be within the transmembrane segment S2 of the fourth homologous domain; Has not been previously published as pathogenic or benign to our knowledge |