Submissions for variant NM_007254.4(PNKP):c.1385G>C (p.Arg462Pro)

dbSNP: rs376854895

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188458	SCV000242072	uncertain significance	not provided	2024-09-10	criteria provided, single submitter	clinical testing	Observed in a patient with ataxia and oculomotor apraxia type 4 who also harbored a second PNKP variant in trans (PMID: 27066586); 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: 31436889, 29891053, 22508754, 27232581, 27066586, 30956058)
Illumina Laboratory Services, Illumina	RCV000306618	SCV000414339	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.
Ambry Genetics	RCV000622668	SCV000742368	likely pathogenic	Inborn genetic diseases	2024-12-24	criteria provided, single submitter	clinical testing	The c.1385G>C (p.R462P) alteration is located in exon 15 (coding exon 14) of the PNKP gene. This alteration results from a G to C substitution at nucleotide position 1385, causing the arginine (R) at amino acid position 462 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.013% (25/192352) total alleles studied. The highest observed frequency was 0.229% (20/8732) of Ashkenazi Jewish alleles. This variant has been identified in the homozygous state and/or in conjunction with other PNKP variant(s) in individual(s) with features consistent with PNKP-related neurological disorder; in at least one instance, the variants were identified in trans (Paucar, 2016; Nair, 2016; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692070	SCV000819877	likely pathogenic	Developmental and epileptic encephalopathy, 12	2024-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 462 of the PNKP protein (p.Arg462Pro). This variant is present in population databases (rs376854895, gnomAD 0.2%). This missense change has been observed in individuals with PNKP-related conditions (PMID: 27066586, 27232581; internal data). ClinVar contains an entry for this variant (Variation ID: 206414). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000188458	SCV001449562	likely pathogenic	not provided	2015-02-19	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000306618	SCV001423184	not provided	Microcephaly, seizures, and developmental delay		no assertion provided	phenotyping only	Variant interpretted as Likely pathogenic and reported on 04-19-2017 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.