Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000188909 | SCV000242539 | uncertain significance | not provided | 2015-12-22 | criteria provided, single submitter | clinical testing | The F1033S variant in the SCN1A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The F1033S variant 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 F1033S 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. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret F1033S as a variant of uncertain significance. |
| Fulgent Genetics, |
RCV002478662 | SCV000895305 | uncertain significance | Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2; Developmental and epileptic encephalopathy 6B | 2022-04-05 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002514044 | SCV003029404 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2024-10-15 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1033 of the SCN1A protein (p.Phe1033Ser). This variant is present in population databases (rs796052992, gnomAD 0.002%). 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: 206796). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN1A protein function. 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. |