Submissions for variant NM_007254.4(PNKP):c.1288_1294dup (p.Ala432fs)

dbSNP: rs796052860

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188470	SCV000242084	pathogenic	not provided	2013-10-14	criteria provided, single submitter	clinical testing	The c.1288_1294dupAGCCGCG mutation in the PNKP gene causes a frameshift starting with codon Alanine 432, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Ala432GlufsX64. This mutation is predicted to cause loss of normal protein function through protein truncation, as 90 amino acids are replaced by 63 incorrect amino acids. Although this mutation has not been previously reported to our knowledge, it is expected to be a pathogenic mutation. The variant is found in INFANT-EPI panel(s).
Ambry Genetics	RCV002381634	SCV002690161	pathogenic	Inborn genetic diseases	2017-08-07	criteria provided, single submitter	clinical testing	The c.1288_1294dupAGCCGCG pathogenic mutation, located in coding exon 13 of the PNKP gene, results from a duplication of AGCCGCG at nucleotide position 1288, causing a translational frameshift with a predicted alternate stop codon (p.A432Efs*64). Based on Ambry internal analysis, this mutation significantly destabilizes this protein structure. This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV003638640	SCV004389216	pathogenic	Developmental and epileptic encephalopathy, 12	2023-08-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala432Glufs*64) in the PNKP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 amino acid(s) of the PNKP protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. ClinVar contains an entry for this variant (Variation ID: 206426). This variant disrupts a region of the PNKP protein in which other variant(s) (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. For these reasons, this variant has been classified as Pathogenic.