ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.670C>T (p.Arg224Cys)

gnomAD frequency: 0.00007  dbSNP: rs761117623
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766603 SCV000242046 uncertain significance not provided 2021-01-11 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago RCV000188433 SCV000596487 uncertain significance not specified 2017-02-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001219120 SCV001391041 uncertain significance Developmental and epileptic encephalopathy, 12 2022-09-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 224 of the PNKP protein (p.Arg224Cys). This variant is present in population databases (rs761117623, gnomAD 0.02%). 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: 206391). 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 C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Baylor Genetics RCV001335538 SCV001528706 uncertain significance Ataxia - oculomotor apraxia type 4 2018-02-12 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics RCV002362985 SCV002666740 uncertain significance Inborn genetic diseases 2018-06-21 criteria provided, single submitter clinical testing The p.R224C variant (also known as c.670C>T), located in coding exon 6 of the PNKP gene, results from a C to T substitution at nucleotide position 670. The arginine at codon 224 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well 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.

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