Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000413789 | SCV000491879 | uncertain significance | not specified | 2016-12-02 | criteria provided, single submitter | clinical testing | The R356Q variant in the KCNT1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R356Q variant was not observed in approximately 6500 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 R356Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R356Q as a variant of uncertain significance |
| Labcorp Genetics |
RCV000554518 | SCV000652900 | likely pathogenic | Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5 | 2025-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 356 of the KCNT1 protein (p.Arg356Gln). This variant is present in population databases (rs758152252, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with KCNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 373294). 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) indicates that this missense variant is not expected to disrupt KCNT1 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg356 amino acid residue in KCNT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25326635, 31532594; internal data). 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. |
| Genome- |
RCV002270240 | SCV002554738 | uncertain significance | Developmental and epileptic encephalopathy, 14 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV002270241 | SCV002554739 | uncertain significance | Autosomal dominant nocturnal frontal lobe epilepsy 5 | 2022-03-15 | criteria provided, single submitter | clinical testing |