Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000414000 | SCV000491762 | uncertain significance | not specified | 2016-11-11 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the KCNQ2 gene. The A667V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It 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, and it was not observed with any significant frequency in the 1000 Genomes Project. This substitution alters a conserved residue predicted to be within the C-terminal cytoplasmic domain. However, the A667V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. 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 | RCV001299367 | SCV001488453 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2023-03-14 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 667 of the KCNQ2 protein (p.Ala667Val). ClinVar contains an entry for this variant (Variation ID: 373184). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. |