Submissions for variant NM_007254.4(PNKP):c.1360C>A (p.Leu454Met)

dbSNP: rs200611702

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723672	SCV000113435	uncertain significance	not provided	2017-09-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000723672	SCV000242029	likely benign	not provided	2020-11-16	criteria provided, single submitter	clinical testing	Identified in a patient with ataxia who was heterozygous for L454M (referred to as c.1160C>A, p.Leu454Met due to the use of alternative nomenclature) and did not have another PNKP variant; this individual also had variants in two other genes that may have been responsible for the phenotype (Algahtani et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30881862)
Genetic Services Laboratory, University of Chicago	RCV000188416	SCV000248540	uncertain significance	not specified	2014-10-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000366061	SCV000414340	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.
Invitae	RCV000472592	SCV000549896	uncertain significance	Developmental and epileptic encephalopathy, 12	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 454 of the PNKP protein (p.Leu454Met). This variant is present in population databases (rs200611702, 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: 95478). 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 not expected to disrupt PNKP protein function with a negative predictive value of 80%. 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.
Athena Diagnostics	RCV000723672	SCV000614682	uncertain significance	not provided	2018-09-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002316250	SCV000850655	likely benign	Inborn genetic diseases	2024-02-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Mayo Clinic Laboratories, Mayo Clinic	RCV000723672	SCV001713015	uncertain significance	not provided	2021-08-31	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000188416	SCV001984381	likely benign	not specified	2020-09-24	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002055206	SCV002495899	uncertain significance	Microcephaly, seizures, and developmental delay; Ataxia - oculomotor apraxia type 4	2021-11-23	criteria provided, single submitter	clinical testing	PNKP NM_007254.3 exon 15 p.Leu454Met (c.1360C>A): This variant has been reported in the literature in 1 individual with ataxia (Algahtani 2019 PMID:30881862); of note, this individual also carried several other variants of uncertain significance. This variant is present in 0.1% (71/68018) of European alleles in the Genome Aggregation Database, as well as a 1 homozygote (https://gnomad.broadinstitute.org/variant/19-49861634-G-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:95478). Evolutionary conservation for this variant is unclear; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Revvity Omics, Revvity	RCV000723672	SCV004237863	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000723672	SCV004934117	likely benign	not provided	2024-04-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000723672	SCV001932865	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000723672	SCV001973345	likely benign	not provided		no assertion criteria provided	clinical testing