ClinVar Miner

Submissions for variant NM_007254.3(PNKP):c.1385G>C (p.Arg462Pro) (rs376854895)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622668 SCV000742368 likely pathogenic Inborn genetic diseases 2017-04-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
GeneDx RCV000188458 SCV000242072 uncertain significance not provided 2013-10-04 criteria provided, single submitter clinical testing p.Arg462Pro (CGG>CCG): c.1385 G>C in exon 15 of the PNKP gene (NM_007254.2) The Arg462Pro missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid substitution is non-conservative, as a positively charged, polar Arginine residue is replaced by an uncharged, non-polar Proline residue and the gain of a Proline may affect the secondary structure of the PNKP protein. Arg462Pro alters a conserved position in the kinase domain; however, missense mutations have not been reported in this region of the protein. In addition, in silico analysis is inconsistent with regard to the effect this variant may have on protein structure/function. Therefore, based on the currently available information, it is unclear whether Arg462Pro is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000306618 SCV000414339 uncertain significance Epileptic encephalopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000692070 SCV000819877 uncertain significance Early infantile epileptic encephalopathy 12 2018-02-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 462 of the PNKP protein (p.Arg462Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs376854895, ExAC 0.03%). This variant has been reported in individuals affected with PNKP-related conditions (PMID: 27066586, 27232581). ClinVar contains an entry for this variant (Variation ID: 206414). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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