Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000188427 | SCV000242040 | uncertain significance | not provided | 2014-04-02 | criteria provided, single submitter | clinical testing | p.Pro136Leu (CCG>CTG): c.407 C>T in exon 4 of the PNKP gene (NM_007254.2) A variant of unknown significance has been identified in the PNKP gene. The P136L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The P136L variant was not observed with any significant frequency in approximately 2,200 individuals of African American ancestry in the NHLBI Exome Sequencing Project. The P136L variant is semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with epilepsy. 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 INFANT-EPI,EPILEPSY panel(s). |
| Invitae | RCV001236454 | SCV001409177 | uncertain significance | Developmental and epileptic encephalopathy, 12 | 2022-09-13 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 136 of the PNKP protein (p.Pro136Leu). This variant is present in population databases (rs11555414, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. ClinVar contains an entry for this variant (Variation ID: 206385). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PNKP protein function. 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. |