Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000725145 | SCV000242044 | uncertain significance | not provided | 2014-05-30 | criteria provided, single submitter | clinical testing | p.Ile222Met (ATC>ATG): c.666 C>G in exon 7 of the PNKP gene (NM_007254.2) A variant of unknown significance has been identified in the PNKP gene. The I222M 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. This substitution occurs at a position that is highly conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the I222M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. 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). |
Eurofins Ntd Llc |
RCV000725145 | SCV000334434 | uncertain significance | not provided | 2015-09-01 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000623130 | SCV000742725 | uncertain significance | Inborn genetic diseases | 2017-09-21 | criteria provided, single submitter | clinical testing | The p.I222M variant (also known as c.666C>G), located in coding exon 6 of the PNKP gene, results from a C to G substitution at nucleotide position 666. The isoleucine at codon 222 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Labcorp Genetics |
RCV001857631 | SCV002201191 | uncertain significance | Developmental and epileptic encephalopathy, 12 | 2021-03-22 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with PNKP-related conditions. ClinVar contains an entry for this variant (Variation ID: 206389). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs587784369, ExAC 0.002%). This sequence change replaces isoleucine with methionine at codon 222 of the PNKP protein (p.Ile222Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. |