Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000187900 | SCV000241502 | uncertain significance | not provided | 2014-07-23 | criteria provided, single submitter | clinical testing | p.Pro420Arg (P420R) CCG>CGG: c.1259 C>G in exon 12 of the KCNQ2 gene (NM_172107.2) The P420R variant has not been published as a mutation, nor has it been reported as a benign polymorphism 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. The P420R 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. However, this substitution occurs at a position that is not conserved across species, and Arginine is observed at this position in other mammalian species. Additionally, in silico analysis predicts this variant likely does not alter the protein structure/function.The identification of P420R suggests that P420R may be a benign variant not associated with the child's phenotype; however, the possibility that it is a disease-associated mutation cannot be excluded since some individuals with KCNQ2 mutations never develop seizures due to incomplete penetrance. Therefore, the identification of P420R in this unaffected parent does not clarify the clinical significance of the variant. The variant is found in EPILEPSY panel(s). |
| Invitae | RCV001857619 | SCV002116739 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2022-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 420 of the KCNQ2 protein (p.Pro420Arg). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 205903). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). |