Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000497350 | SCV000590224 | uncertain significance | not provided | 2017-06-02 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the KCNQ3 gene. The T846M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T846M 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 T846M 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 across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Invitae | RCV001857013 | SCV002194244 | uncertain significance | Benign neonatal seizures | 2023-05-16 | criteria provided, single submitter | clinical testing | 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. 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) has been performed at Invitae 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 KCNQ3 protein function. ClinVar contains an entry for this variant (Variation ID: 432492). This variant has not been reported in the literature in individuals affected with KCNQ3-related conditions. This variant is present in population databases (rs765623435, gnomAD 0.006%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 846 of the KCNQ3 protein (p.Thr846Met). |