Submissions for variant NM_007254.4(PNKP):c.1549C>T (p.Gln517Ter)

gnomAD frequency: 0.00019  dbSNP: rs774995635

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001059483	SCV001224107	pathogenic	Developmental and epileptic encephalopathy, 12	2023-07-31	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individuals with clinical features of Charcot-Marie-Tooth disease (PMID: 30039206). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 854429). For these reasons, this variant has been classified as Pathogenic. This variant is present in population databases (rs774995635, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This sequence change creates a premature translational stop signal (p.Gln517*) in the PNKP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the PNKP protein.
GeneDx	RCV001552324	SCV001772992	uncertain significance	not provided	2023-04-25	criteria provided, single submitter	clinical testing	Observed in apparent homozygous state in members of a consanguineous family and observed multiple times with another PNKP variantin unrelated patients in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes; all are described as having Charcot Marie Tooth disease type 2 (Leal et al., 2018); Nonsense variant predicted to result in protein truncation as the last 5 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 19290556, 30956058, 31436889, 22508754, 30039206)
Ambry Genetics	RCV002402427	SCV002709411	uncertain significance	Inborn genetic diseases	2020-03-31	criteria provided, single submitter	clinical testing	The p.Q517* variant (also known as c.1549C>T), located in coding exon 16 of the PNKP gene, results from a C to T substitution at nucleotide position 1549. This changes the amino acid from a glutamine to a stop codon within coding exon 16. In a large Costa Rican family, this variant was homozygous in individuals with Charcot-Marie-Tooth (CMT) disease with axonal neuropathy and autosomal recessive pattern of inheritance; all the affected individuals were also homozygous for the p.A335V MED25 variant (Leal A et al. Neurogenetics, 2018 12;19:215-225). In five other Costa Rican families with CMT, this variant was compound heterozygous with another PNKP nonsense variant in affected individuals; these individuals were also heterozygous for the p.A335V MED25 variant, suggesting a common ancestral haploytpe. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of PNKP, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 5 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. Based on available evidence to date, the clinical significance of this alteration remains unclear.
OMIM	RCV001093541	SCV001250590	pathogenic	Charcot-Marie-Tooth disease type 2B2	2020-05-07	no assertion criteria provided	literature only
Diagnostic Laboratory, Strasbourg University Hospital	RCV002275195	SCV002562837	pathogenic	Abnormal cerebral morphology		no assertion criteria provided	clinical testing