Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000548145 | SCV000660388 | uncertain significance | Developmental and epileptic encephalopathy, 12 | 2022-04-29 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 478624). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 408 of the PNKP protein (p.Thr408Lys). 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 variant has not been reported in the literature in individuals affected with PNKP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant disrupts the p.Thr408 amino acid residue in PNKP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25728773, 27066567). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |