Submissions for variant NM_007254.4(PNKP):c.188C>T (p.Ala63Val)

gnomAD frequency: 0.00047  dbSNP: rs3739173

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147356	SCV000194731	uncertain significance	Microcephaly, seizures, and developmental delay	2013-11-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000726472	SCV000242021	uncertain significance	not provided	2023-03-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22508754)
Eurofins Ntd Llc (ga)	RCV000726472	SCV000344914	uncertain significance	not provided	2016-09-08	criteria provided, single submitter	clinical testing
Invitae	RCV000466098	SCV000549895	uncertain significance	Developmental and epileptic encephalopathy, 12	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 63 of the PNKP protein (p.Ala63Val). This variant is present in population databases (rs3739173, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 159792). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000147356	SCV000743937	likely benign	Microcephaly, seizures, and developmental delay	2016-03-30	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000147356	SCV000745399	likely benign	Microcephaly, seizures, and developmental delay	2016-05-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312973	SCV000847577	uncertain significance	Inborn genetic diseases	2018-09-16	criteria provided, single submitter	clinical testing	The p.A63V variant (also known as c.188C>T), located in coding exon 2 of the PNKP gene, results from a C to T substitution at nucleotide position 188. The alanine at codon 63 is replaced by valine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Illumina Laboratory Services, Illumina	RCV000147356	SCV001288758	uncertain significance	Microcephaly, seizures, and developmental delay	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV000726472	SCV001713025	uncertain significance	not provided	2023-04-19	criteria provided, single submitter	clinical testing	BP4
CeGaT Center for Human Genetics Tuebingen	RCV000726472	SCV002543963	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726472	SCV004236197	uncertain significance	not provided	2023-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987375	SCV004804328	uncertain significance	not specified	2024-01-09	criteria provided, single submitter	clinical testing	Variant summary: PNKP c.188C>T (p.Ala63Val) results in a non-conservative amino acid change located in the PNK, FHA domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 251490 control chromosomes. To our knowledge, no occurrence of c.188C>T in individuals affected with PNKP-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 159792). Based on the evidence outlined above, the variant was classified as uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000147356	SCV000733908	likely benign	Microcephaly, seizures, and developmental delay		no assertion criteria provided	clinical testing