ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.1385G>C (p.Arg462Pro)

dbSNP: rs376854895
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188458 SCV000242072 uncertain significance not provided 2021-02-15 criteria provided, single submitter clinical testing Observed in a patient with ataxia and oculomotor apraxia type 4 who also harbored a second PNKP variant in trans (Paucar et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27066586, 27232581, 31436889, 29891053)
Illumina Laboratory Services, Illumina RCV000306618 SCV000414339 uncertain significance Microcephaly, seizures, and developmental delay 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics RCV000622668 SCV000742368 likely pathogenic Inborn genetic diseases 2017-04-06 criteria provided, single submitter clinical testing
Invitae RCV000692070 SCV000819877 likely pathogenic Developmental and epileptic encephalopathy, 12 2023-07-30 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 206414). This missense change has been observed in individuals with PNKP-related conditions (PMID: 27066586, 27232581; Invitae). This variant is present in population databases (rs376854895, gnomAD 0.2%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 462 of the PNKP protein (p.Arg462Pro).
Clinical Genetics and Genomics, Karolinska University Hospital RCV000188458 SCV001449562 likely pathogenic not provided 2015-02-19 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000306618 SCV001423184 not provided Microcephaly, seizures, and developmental delay no assertion provided phenotyping only Variant interpretted as Likely pathogenic and reported on 04-19-2017 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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