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	likely pathogenic	not provided	2024-08-06	criteria provided, single submitter	clinical testing	Reported previously in the compound heterozygous state in a patient with microcephaly, seizures, severe developmental delay, abnormal brain MRI, absent speech, inability to walk, short stature, and dysmorphic features and in a patient with epilepsy, global developmental delay, microcephaly, and a high-grade brain tumor (PMID: 35354845, 37916443); Reported previously in a patient with microcephaly, delayed motor development, regression of motor skills, inability to walk, intellectual disability, epilepsy and ataxia, who also harbored a second pathogenic variant, phase unknown (PMID: 32980744); Observed in heterozygous state in a patient with epilepsy (PMID: 29655203); 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, 34040816, 35354845, 37916443, 32980744, 29655203, 34697416)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055727	SCV001220131	likely pathogenic	Developmental and epileptic encephalopathy, 12	2024-01-17	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 individuals with clinical features of PNKP-related conditions (PMID: 29655203, 32980744, 34040816, 35354845; Invitae). 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). 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	RCV002371985	SCV002692540	uncertain significance	Inborn genetic diseases	2022-03-09	criteria provided, single submitter	clinical testing	The c.968C>T (p.T323M) alteration is located in exon 11 (coding exon 10) of the PNKP gene. This alteration results from a C to T substitution at nucleotide position 968, causing the threonine (T) at amino acid position 323 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (10/200044) total alleles studied. The highest observed frequency was 0.02% (1/5142) of Other alleles. This alteration was reported in a 7 year old patient with microcephaly, seizures, developmental delay, ataxia, and polyneuropathy (Garrelfs, 2020). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
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.