Total submissions: 14
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000723672 | SCV000113435 | uncertain significance | not provided | 2017-09-14 | criteria provided, single submitter | clinical testing | |
Gene |
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, |
RCV000188416 | SCV000248540 | uncertain significance | not specified | 2014-10-27 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
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. |
Labcorp Genetics |
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, |
RCV000723672 | SCV001713015 | uncertain significance | not provided | 2021-08-31 | criteria provided, single submitter | clinical testing | |
Al Jalila Children’s Genomics Center, |
RCV000188416 | SCV001984381 | likely benign | not specified | 2020-09-24 | criteria provided, single submitter | clinical testing | |
Center for Genomics, |
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, |
RCV000723672 | SCV004237863 | likely benign | not provided | 2023-11-01 | criteria provided, single submitter | clinical testing | |
Genomic Research Center, |
RCV000723672 | SCV004934117 | likely benign | not provided | 2024-04-22 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV000723672 | SCV001932865 | likely benign | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000723672 | SCV001973345 | likely benign | not provided | no assertion criteria provided | clinical testing |