Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000478181 | SCV000574200 | uncertain significance | not provided | 2017-03-20 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the KCNQ2 gene. The R493C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R493C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R493C 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Invitae | RCV001865492 | SCV002164934 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2023-09-15 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 424395). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 493 of the KCNQ2 protein (p.Arg493Cys). This variant is present in population databases (rs759338332, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. 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 KCNQ2 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. |