Submissions for variant NM_007254.4(PNKP):c.865+1G>A

gnomAD frequency: 0.00002  dbSNP: rs762003634

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001992260	SCV002285438	likely pathogenic	Developmental and epileptic encephalopathy, 12	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 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 (rs762003634, gnomAD 0.01%). 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: 1497182). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002625406	SCV003622463	likely pathogenic	Inborn genetic diseases	2022-05-14	criteria provided, single submitter	clinical testing	The c.865+1G>A intronic variant results from a G to A substitution one nucleotide after exon 9 (coding exon 8) of the PNKP gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (5/251250) total alleles studied. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003339880	SCV004047431	likely pathogenic	Microcephaly, seizures, and developmental delay		criteria provided, single submitter	clinical testing	The splice site variant c.865+1G>A in PNKP gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Likely Pathogenic. The c.865+1G>A variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.001990% is reported in gnomAD. The variant affects an invariant splice nucleotide and is expected to cause loss of function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic.