ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.1232C>T (p.Thr411Ile)

gnomAD frequency: 0.00001  dbSNP: rs868384150
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494552 SCV000582798 uncertain significance not provided 2017-05-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PNKP gene. The T411I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T411I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T411I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000557730 SCV000650111 uncertain significance Developmental and epileptic encephalopathy, 12 2017-07-19 criteria provided, single submitter clinical testing 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PNKP-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 411 of the PNKP protein (p.Thr411Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine.

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