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

dbSNP: rs587784365

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000005120	SCV000194720	pathogenic	Microcephaly, seizures, and developmental delay	2014-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000188471	SCV000242085	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect showing that the variant reduces or eliminates PNKP DNA kinase activity (Reynolds et al., 2012); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 98 amino acids are lost and replaced with 48 incorrect amino acids (HGMD); This variant is associated with the following publications: (PMID: 23224214, 25558065, 23921166, 22508754, 25728773, 20118933, 29498415, 28333917, 30956058, 29655203, 30267214, 30214071, 31707899, 31436889, 34402213, 31589614, 31110700, 32504494)
Eurofins Ntd Llc (ga)	RCV000188471	SCV000341338	pathogenic	not provided	2016-05-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706286	SCV000835326	pathogenic	Developmental and epileptic encephalopathy, 12	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr424Glyfs*49) in the PNKP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 98 amino acid(s) of the PNKP protein. This variant is present in population databases (rs587784365, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with microcephaly, early-onset, intractable seizures and developmental delay (MCSZ), ataxia with oculomotor apraxia, and progressive cerebellar atrophy and polyneuropathy (PMID: 20118933, 23224214, 25558065, 25728773). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1250_1251insAACGGGTCGCCATCGAC (p.R418Tfs*55). ClinVar contains an entry for this variant (Variation ID: 4847). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PNKP function (PMID: 22508754). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000005120	SCV001149887	pathogenic	Microcephaly, seizures, and developmental delay	2020-01-16	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV001257702	SCV001434513	pathogenic	Intellectual disability	2020-04-20	criteria provided, single submitter	clinical testing
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles	RCV000005120	SCV001481951	pathogenic	Microcephaly, seizures, and developmental delay	2020-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000188471	SCV001747940	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	PNKP: PM3:Very Strong, PVS1, PM2, PS3:Supporting
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813954	SCV001755558	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000188471	SCV002019447	pathogenic	not provided	2019-12-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415399	SCV002676502	pathogenic	Inborn genetic diseases	2024-09-16	criteria provided, single submitter	clinical testing	The c.1253_1269dup17 (p.T424Gfs*49) alteration, located in exon 14 (coding exon 13) of the PNKP gene, consists of a duplication of GGGTCGCCATCGACAAC at position 1253, causing a translational frameshift with a predicted alternate stop codon after 49 amino acids. This alteration occurs at the 3' terminus of the PNKP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 18% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the c.1253_1269dup17 allele has an overall frequency of 0.017% (38/220830) total alleles studied. The highest observed frequency was 0.029% (29/99720) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in conjunction with other PNKP variants in individuals with features consistent with PNKP-related neurological disorders; in at least one instance, the variants were identified in trans (Shen, 2010; Poulton, 2013; Bras, 2015; Scholz, 2018). 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, 2011). In an assay testing PNKP function, this variant showed a functionally abnormal result (Reynolds, 2012). Based on the available evidence, this alteration is classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000005120	SCV002767068	pathogenic	Microcephaly, seizures, and developmental delay	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-oculomotor apraxia 4 (MIM#616267), and microcephaly, seizures, and developmental delay (MIM#613402). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected (PMID: 22508754). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (38 heterozygotes, 0 homozygotes). (SP) 0600 - Variant results in the loss of part of the annotated AAA domain (PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been described as pathogenic in multiple homozygous and compound heterozygous patients, with either ataxia-oculomotor apraxia 4 or microcephaly, seizures and developmental delay (ClinVar, PMID: 31436889, PMID: 31707899). (SP) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (p.(Ser430Lysfs*39)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000188471	SCV005413373	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	PP1_strong, PP4, PM2, PM3_strong, PS3, PS4_moderate, PVS1_moderate
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV005401280	SCV005908088	pathogenic	Seizure	2025-04-10	criteria provided, single submitter	clinical testing
OMIM	RCV000005120	SCV000025297	pathogenic	Microcephaly, seizures, and developmental delay	2015-03-05	no assertion criteria provided	literature only
OMIM	RCV000167521	SCV000218379	pathogenic	Ataxia - oculomotor apraxia type 4	2015-03-05	no assertion criteria provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000005120	SCV001432380	pathogenic	Microcephaly, seizures, and developmental delay		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000188471	SCV001741757	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000188471	SCV001953183	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000188471	SCV001967955	pathogenic	not provided		no assertion criteria provided	clinical testing