Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000188461 | SCV000242075 | uncertain significance | not provided | 2014-05-08 | criteria provided, single submitter | clinical testing | p.Met477Val (ATG>GTG): c.1429 A>G in exon 16 of the PNKP gene (NM_007254.2) A variant of unknown significance has been identified in the PNKP gene. The M477V 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 M477V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. Missense mutations in other nearby residues have not been reported. However, in silico analysis is inconsistent in its predictions as to whether or not the M477V variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in EPILEPSY panel(s). |
| Invitae | RCV001857634 | SCV002273561 | uncertain significance | Developmental and epileptic encephalopathy, 12 | 2021-10-11 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine with valine at codon 477 of the PNKP protein (p.Met477Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). 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: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine 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: 206417). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. |