ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.883G>A (p.Ala295Thr)

gnomAD frequency: 0.00008  dbSNP: rs368887106
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188439 SCV000242052 uncertain significance not provided 2019-01-14 criteria provided, single submitter clinical testing p.Ala295Thr (GCC>ACC): c.883 G>A in exon 10 of the PNKP gene (NM_007254.2) The Ala295Thr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This variant is a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Threonine residue at a position that is conserved across species in the phosphatase domain of the PNKP protein. However, other missense mutations at nearby codons have not been reported in association with epilepsy. In addition, in silico analysis predicts this variant likely has a benign effect on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Ala295Thr is a disease-causing mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV000804653 SCV000944570 uncertain significance Developmental and epileptic encephalopathy, 12 2024-11-05 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 295 of the PNKP protein (p.Ala295Thr). This variant is present in population databases (rs368887106, gnomAD 0.03%). 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: 206397). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.

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