ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.1295_1298+6del

dbSNP: rs587784366
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000147346 SCV000194721 pathogenic Microcephaly, seizures, and developmental delay 2014-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000188473 SCV000242087 pathogenic not provided 2013-09-19 criteria provided, single submitter clinical testing The c.1295_1298+6delCCAGGTAGCG mutation in the PNKP gene results in the deletion of ten nucleotides at the exon 14/intron 14 boundary, thereby destroying the canonical splice donor site in intron 14. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product if the message is used for protein translation. Although this mutation has not been previously reported to our knowledge, it is considered a disease-causing mutation.The variant is found in CHILD-EPI,EPILEPSY panel(s).
Eurofins Ntd Llc (ga) RCV000188473 SCV000700789 likely pathogenic not provided 2016-06-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825541 SCV000966857 pathogenic Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia 2023-12-19 criteria provided, single submitter clinical testing The c.1295_1298+6del (NM_007254.3 c.1295_1298+6delCCAGGTAGCG) variant in PNKP has been reported in the compound heterozygous state in 1 individual with microcephaly with early onset seizures (MCSZ), in 1 individual with motor neuropathy, and in 2 individuals with ataxia with oculomotor apraxia and segregated with disease in 2 affected relatives from 1 family (Previtali 2019 PMID: 31167812, Kalasova 2019 PMID: 31041400, da Costa 2022 PMID: 35426160). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 159788) and has been identified in 0.06% (3/4832) of South Asian and 0.0029% (2/68006) of European chromosomes by gnomAD (, v.3.1.2). This variant is a deletion of ten nucleotides at the exon 14/intron 14 boundary, thereby destroying the canonical splice donor site in intron 14. It is predicted to cause altered splicing, leading to an abnormal or absent protein. Biallelic loss of function of the PNKP gene has been associated with ataxia with oculomotor apraxia. Functional studies in patient fibroblasts provide some evidence that this variant reduced protein expression and activity and were more susceptible to single strand breaks due to reduced repair activity (Kalasova 2019 PMID: 31041400, Kalasova 2020 PMID: 32504494). In summary, the c.1295_1298+6delCCAGGTAGCG variant in PNKP meets criteria to be classified as pathogenic for PNKP-related disorders, such as autosomal recessive ataxia with oculomotor apraxia, and autosomal recessive microcephaly, seizures and developmental delay. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP1, PS3_Supporting.
Invitae RCV001070856 SCV001236133 pathogenic Developmental and epileptic encephalopathy, 12 2023-12-04 criteria provided, single submitter clinical testing This variant results in the deletion of part of exon 14 (c.1295_1298+6del) of the PNKP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PNKP are known to be pathogenic (PMID: 20118933, 25728773). This variant is present in population databases (rs587784366, gnomAD 0.03%). This variant has been observed in individual(s) with PNKP-related conditions (PMID: 31167812). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 159788). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PNKP function (PMID: 32504494). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000188473 SCV002019446 pathogenic not provided 2021-04-06 criteria provided, single submitter clinical testing

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