ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.1483T>C (p.Phe495Leu)

gnomAD frequency: 0.00003  dbSNP: rs1165689250
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498927 SCV000590693 uncertain significance not provided 2017-06-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PNKP gene. The F495L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The F495Lvariant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). 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. However, the F495L 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 variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV002524104 SCV003490138 uncertain significance Developmental and epileptic encephalopathy, 12 2024-10-30 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 495 of the PNKP protein (p.Phe495Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 432917). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PNKP protein function with a negative predictive value of 80%. 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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