Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000519264 | SCV000621646 | uncertain significance | not provided | 2017-10-27 | criteria provided, single submitter | clinical testing | The E366D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E366D variant is not observed in large population cohorts (Lek et al., 2016). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. |
| Invitae | RCV000576183 | SCV000677004 | uncertain significance | Developmental and epileptic encephalopathy, 12 | 2023-08-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 366 of the PNKP protein (p.Glu366Asp). This variant is not present in population databases (gnomAD no frequency). 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: 452807). 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. |
| Ambry Genetics | RCV002456021 | SCV002737258 | uncertain significance | Inborn genetic diseases | 2019-05-12 | criteria provided, single submitter | clinical testing | The p.E366D variant (also known as c.1098G>C), located in coding exon 11 of the PNKP gene, results from a G to C substitution at nucleotide position 1098. The glutamic acid at codon 366 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |