Submissions for variant NM_007254.4(PNKP):c.968C>T (p.Thr323Met)

gnomAD frequency: 0.00005  dbSNP: rs372148913

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147374	SCV000194751	likely pathogenic	Microcephaly, seizures, and developmental delay	2013-08-05	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000724557	SCV000225364	uncertain significance	not provided	2015-02-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000724557	SCV000242054	pathogenic	not provided	2025-01-23	criteria provided, single submitter	clinical testing	Observed multiple times with a second PNKP variant in unrelated patients with features of a PNKP-related disorder referred for genetic testing at GeneDx and in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 35354845, 37916443, 32980744); Published functional studies demonstrate a damaging effect and show that this variant causes a significant loss of both 5'-kinase and 3'-phosphatase activity, increases radiation sensitivity, and impairs double strand DNA repair in vitro (PMID: 35354845); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22508754, 35354845, 37916443, 29655203, 34697416, 34040816, 32980744)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055727	SCV001220131	pathogenic	Developmental and epileptic encephalopathy, 12	2024-06-25	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 323 of the PNKP protein (p.Thr323Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of PNKP-related conditions (PMID: 29655203, 32980744, 34040816, 35354845; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 159803). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PNKP protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PNKP function (PMID: 35354845). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002371985	SCV002692540	likely pathogenic	Inborn genetic diseases	2024-10-03	criteria provided, single submitter	clinical testing	The p.T323M variant (also known as c.968C>T), located in coding exon 10 of the PNKP gene, results from a C to T substitution at nucleotide position 968. The threonine at codon 323 is replaced by methionine, an amino acid with similar properties. This variant has been identified homozygous and in conjunction with other PNKP variants in individuals with seizures, microcephaly, global developmental delay, dyskinesia, abnormal MRI, lissencephaly, and/or polymicrogyria, and other clinical features consistent with PNKP-related neurodevelopmental disorder; in at least one instance, the variants were identified in trans (Lindy AS et al. Epilepsia, 2018 May;59:1062-1071; Garrelfs MR et al. Pediatr Neurol, 2020 Dec;113:26-3; Marcilla Vázquez C et al. J Pediatr Genet, 2021 Jun;10:164-172; Jiang B et al. Sci Rep, 2022 Mar;12:5386; Thuresson AC et al. Mol Genet Genomic Med, 2024 Jan;12:e2295; External communication, 2024). In multiple assays testing PNKP function, this variant showed functionally abnormal results (Jiang B et al. Sci Rep, 2022 Mar;12:5386). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Revvity Omics, Revvity	RCV000724557	SCV003811224	uncertain significance	not provided	2021-03-25	criteria provided, single submitter	clinical testing
Hadassah Hebrew University Medical Center	RCV003387771	SCV004099512	likely pathogenic	Ataxia - oculomotor apraxia type 4		criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544343	SCV004765018	uncertain significance	PNKP-related disorder	2024-02-03	no assertion criteria provided	clinical testing	The PNKP c.968C>T variant is predicted to result in the amino acid substitution p.Thr323Met. This variant has been reported in the homozygous state, in combination with an additional variant (phase not provided), or with no zygosity provided, in individuals with microcephaly, seizures, and developmental delay (Marcilla Vázquez C et al 2020. PubMed ID: 34040816; Jiang B et al 2022. PubMed ID: 35354845; Lindy et al 2018. PubMed ID: 29655203 Supplemental Table 4; Garrelfs et al. 2020. PubMed ID: 32980744). In vitro studies using an overexpression system suggested that this variant may reduce protein function by multiple mechanisms (Jiang B et al 2022. PubMed ID: 35354845). This variant is reported in 0.0092% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.