ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.1253_1269dup (p.Thr424fs) (rs587784365)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000188471 SCV000341338 pathogenic not provided 2016-05-13 criteria provided, single submitter clinical testing
GeneDx RCV000188471 SCV000242085 pathogenic not provided 2018-10-10 criteria provided, single submitter clinical testing The c.1253_1269dup17 pathogenic variant in the PNKP gene has been reported previously in multiple individuals with microcephaly, infantile seizures, and developmental delay (MCSZ) who were either homozygous for the variant or compound heterozygous for this variant and another PNKP pathogenic variant on the opposite allele (Shen et al., 2010; Oegema et al., 2014). Functional studies show that c.1253_1269dup17 reduces or eliminates PNKP DNA kinase activity (Reynolds et al., 2012). The duplication causes a frameshift starting with codon Threonine 424, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 49 of the new reading frame, denoted p.Thr424GlyfsX49. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 98 amino acid residues are replaced by 48 aberrant resides. Therefore, c.1253_1269dup17 is interpreted to be a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000005120 SCV000194720 pathogenic Early infantile epileptic encephalopathy 10 2014-06-05 criteria provided, single submitter clinical testing
Invitae RCV000706286 SCV000835326 pathogenic Early infantile epileptic encephalopathy 12 2018-03-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PNKP gene (p.Thr424Glyfs*49). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 98 amino acids of the PNKP protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in several families and individuals affected with microcephaly, early-onset, intractable seizures and developmental delay (MCSZ), ataxia with oculomotor apraxia, and progressive cerebellar atrophy and polyneuropathy (PMID: 20118933, 25558065, 25728773, 23224214). This variant is also known as c.1250_1251insAACGGGTCGCCATCGAC (p.R418Tfs*55) in the literature. ClinVar contains an entry for this variant (Variation ID: 4847). Experimental studies have shown that this variant impairs PNKP DNA kinase activity (PMID: 22508754). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000005120 SCV000025297 pathogenic Early infantile epileptic encephalopathy 10 2015-03-05 no assertion criteria provided literature only
OMIM RCV000167521 SCV000218379 pathogenic Ataxia-oculomotor apraxia 4 2015-03-05 no assertion criteria provided literature only

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