Submissions for variant NM_007254.4(PNKP):c.1278_1291del (p.Asp427fs)

dbSNP: rs764379536

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598923	SCV000710789	likely pathogenic	not provided	2018-02-28	criteria provided, single submitter	clinical testing	The c.1278_1291del14 variant in the PNKP gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1278_1291del14 variant causes a frameshift starting with codon Aspartic acid 427, changes this amino acid to a Arginine residue, and creates a premature Stop codon at position 62 of the new reading frame, denoted p.Asp427ArgfsX62. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1278_1291del14 variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1278_1291del14 as a likely pathogenic variant.
Ambry Genetics	RCV002448841	SCV002682949	pathogenic	Inborn genetic diseases	2019-03-29	criteria provided, single submitter	clinical testing	The c.1278_1291del14 pathogenic mutation, located in coding exon 13 of the PNKP gene, results from a deletion of 14 nucleotides at nucleotide positions 1278 to 1291, causing a translational frameshift with a predicted alternate stop codon (p.D427Rfs*62). This frameshift occurs at the 3' terminus of PNKP, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 95 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. However, variants resulting in similar proteins have been reported in individuals with microcephaly, seizures and developmental delay, as well as ataxia with oculomotor apraxia type 4 (Shen J et al. Nat. Genet., 2010 Mar;42:245-9; Bras J et al. Am. J. Hum. Genet., 2015 Mar;96:474-9). One of those variants (c.1253_1269dup17) has also been shown to lose DNA kinase activity in functional studies (Reynolds JJ et al. Nucleic Acids Res., 2012 Aug;40:6608-19). Based on our internal structural assessment, this alteration results in loss of large parts of the polynucleotide kinase domain, including helices involved in DNA and NTP binding (Garces F et al. Mol. Cell, 2011 Nov;44:385-96). In addition, this variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV002532707	SCV003300618	pathogenic	Developmental and epileptic encephalopathy, 12	2023-04-15	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 504465). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. This variant is present in population databases (rs764379536, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Asp427Argfs*62) in the PNKP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the PNKP protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PNKP protein in which other variant(s) (p.Gln517*) have been determined to be pathogenic (PMID: 30039206). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing.