ClinVar Miner

Submissions for variant NM_000298.6(PKLR):c.1529G>A (p.Arg510Gln) (rs113403872)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224660 SCV000280891 pathogenic not provided 2014-06-25 criteria provided, single submitter clinical testing
GeneDx RCV000224660 SCV000329969 pathogenic not provided 2015-12-21 criteria provided, single submitter clinical testing The R510Q pathogenic variant in the PKLR gene has been reported as the most common pathogenic variant association with pyruvate kinase deficiency in Northern European populations, seen in affected individuals who were homozygous or compound heterozygous for the R510Q variant (Lenzner et al., 1997; Baronciani et at., 1993). Functional studies showed the R510Q protein had deceased stability toward heat and was more susceptible to ATP inhibition, leading to enzyme instability and decreased enzyme levels in the cell (Wang et al., 2001). The R510Q variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R510Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. We interpret R510Q as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000001575 SCV000348594 pathogenic Pyruvate kinase deficiency of red cells 2016-06-14 criteria provided, single submitter clinical testing The c.1529G>A (p.Arg510Gln) variant has been described as the most common pyruvate kinase (PK) deficiency variant in the European population. Across a selection of the available literature, the p.Arg510Gln variant has been identified in at least 43 patients in a homozygous state, 21 patients in a compound heterozygous state, and one patient in a heterozygous state (Baronciani et al. 1993; Baronciani et al. 1995; Lenzner et al. 1997; van Solinge et al. 1997; van Wijk et al. 2003; Rider et al. 2011). Heterozygous parents of the patients, though not affected, were shown to have decreased levels of pyruvate kinase activity (van Solinge et al. 1997). The p.Arg510Gln variant was absent from 150 controls but is reported at a frequency of 0.00093 in the European American population of the Exome Sequencing Project. Functional studies demonstrated that the variant has decreased thermostability, accelerated intracellular proteolytic degradation, and is more susceptible to ATP inhibition (Lenzner et al 1997; Wang et al. 2001). Based on the collective evidence, the p.Arg510Gln variant is classified as pathogenic for pyruvate kinase deficiency.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224660 SCV000863295 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000208 SCV001156713 pathogenic not specified 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000001575 SCV000021731 pathogenic Pyruvate kinase deficiency of red cells 2001-11-15 no assertion criteria provided literature only

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