Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000485178 | SCV000573647 | uncertain significance | not provided | 2017-02-24 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the PNKP gene. The A295V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A295V 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). This substitution occurs at a position that is conserved in mammals. However, the A295V 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 | RCV001369311 | SCV001565745 | uncertain significance | Developmental and epileptic encephalopathy, 12 | 2022-06-29 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 423891). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PNKP-related conditions. This variant is present in population databases (rs753695701, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 295 of the PNKP protein (p.Ala295Val). |