ClinVar Miner

Submissions for variant NM_000298.6(PKLR):c.1706G>A (p.Arg569Gln)

gnomAD frequency: 0.00119  dbSNP: rs61755431
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001101366 SCV001257968 uncertain significance Pyruvate kinase deficiency of red cells 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001811654 SCV001471581 uncertain significance not provided 2020-05-11 criteria provided, single submitter clinical testing
Invitae RCV001811654 SCV002186831 uncertain significance not provided 2023-10-15 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 569 of the PKLR protein (p.Arg569Gln). This variant is present in population databases (rs61755431, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of pyruvate kinase deficiency (PMID: 15953013, 19085939, 21794208, 31974203, 32043619, 33631127). ClinVar contains an entry for this variant (Variation ID: 876509). 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 PKLR protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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.
Revvity Omics, Revvity RCV001811654 SCV003808478 uncertain significance not provided 2023-05-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323797 SCV004030164 uncertain significance not specified 2023-07-14 criteria provided, single submitter clinical testing Variant summary: PKLR c.1706G>A (p.Arg569Gln) results in a conservative amino acid change located in the Pyruvate kinase, C-terminal domain (IPR015795) 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 0.0011 in 250772 control chromosomes in the gnomAD database, including 1 homozygote. This frequency does not allow any conclusion about variant significance. c.1706G>A has been reported in the literature in the compound heterozygous state in individuals affected with various severities of Pyruvate Kinase Deficiency Of Red Cells (e.g. van Wijk_2009, Lyon_2011, Milanesio_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15953013, 21794208, 33631127, 31974203, 19085939, 32043619). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV001811654 SCV004224647 uncertain significance not provided 2022-12-19 criteria provided, single submitter clinical testing PP3

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