Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000513029 | SCV000590637 | uncertain significance | not provided | 2018-05-21 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the SCN1A gene. The G1233D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A different missense substitution at the same position (G1233R) has been reported previously in an individual with severe myoclonic epilepsy of infancy; however, parental studies were not performed (Nabbout et al., 2003). The G1233D variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G1233D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution alters a conserved position that is predicted to be within the transmembrane segment S1 of the third homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (S1231T/R, A1236P, E1238D) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Ce |
RCV000513029 | SCV000608982 | likely pathogenic | not provided | 2017-06-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002527157 | SCV003197357 | pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2022-08-19 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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: 432867). This missense change has been observed in individual(s) with clinical features of SCN1A-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1233 of the SCN1A protein (p.Gly1233Asp). |