ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.1391G>C (p.Arg464Pro)

dbSNP: rs377619541
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188459 SCV000242073 uncertain significance not provided 2013-09-27 criteria provided, single submitter clinical testing p.Arg464Pro (CGA>CCA): c.1391 G>C in exon 16 of the PNKP gene (NM_007254.2) The Arg464Pro missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution of a positively charged Arginine residue with an uncharged Proline residue, and the addition of a Proline, which has a unique ring structure, may impact the secondary structure of the protein. The variant alters a position that is conserved across species in the kinase domain, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations have not been published in the kinase domain to date. Therefore, based on the currently available information, it is unclear whether Arg464Pro is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV001857633 SCV002124241 uncertain significance Developmental and epileptic encephalopathy, 12 2022-11-28 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PNKP protein function. ClinVar contains an entry for this variant (Variation ID: 206415). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. This variant is present in population databases (rs377619541, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 464 of the PNKP protein (p.Arg464Pro).
Fulgent Genetics, Fulgent Genetics RCV002492866 SCV002790370 uncertain significance Charcot-Marie-Tooth disease type 2B2; Microcephaly, seizures, and developmental delay; Ataxia - oculomotor apraxia type 4 2021-09-17 criteria provided, single submitter clinical testing

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