ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.406C>G (p.Pro136Ala)

dbSNP: rs759530456
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188426 SCV000242039 uncertain significance not provided 2012-06-21 criteria provided, single submitter clinical testing p.Pro136Ala (CCG>GCG): c.406 C>G in exon 4 of the PNKP gene (NM_007254.2) The Pro136Ala missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Pro136Ala in approximately 5,000 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Although both Proline and Alanine are uncharged, non-polar amino acids, the loss of a Proline residue may alter the secondary structure of the protein. However, Pro136Ala alters a position that is not conserved in PNKP or in related proteins, and mutations have not been previously published in this region of the protein. Additionally, multiple in silico algorithms predict Pro136Ala is likely not pathogenic. Therefore, based on the currently available information, it is unclear whether Pro136Ala is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV000648407 SCV000770227 uncertain significance Developmental and epileptic encephalopathy, 12 2022-03-19 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 136 of the PNKP protein (p.Pro136Ala). This variant is present in population databases (rs759530456, gnomAD 0.0009%). 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: 206384). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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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