ClinVar Miner

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

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Total submissions: 9
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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 none provided 2020-07-30 criteria provided, single submitter clinical testing The PKLR c.1529G>A; p.Arg510Gln variant (rs113403872) is reported in both the homozygous or compound heterozygous state in multiple individuals affected with pyruvate kinase deficiency and is considered to be the most common cause of pyruvate kinase deficiency in European populations (Baronciani 1993, Baronciani 1995, Lenzner 1997, van Solinge 1997, van Wijk 2003). Functional analyses of the variant protein shows decreased thermostability, accelerated intracellular proteolytic degradation, and increased susceptibility to ATP inhibition (Lenzner 1997, Wang 2001). This variant is reported as pathogenic by four laboratories in ClinVar (Variation ID: 1511). This variant is found predominantly in the non-Finnish European population with an overall allele frequency of 0.073% (92/126696 alleles, including no homozygotes) in the Genome Aggregation Database. The arginine at codon 510 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Baronciani L and Beutler E. Analysis of pyruvate kinase-deficiency mutations that produce nonspherocytic hemolytic anemia. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4324-7. Baronciani L and Beutler E. Molecular study of pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia. J Clin Invest. 1995 Apr;95(4):1702-9. Lenzner C et al. Molecular analysis of 29 pyruvate kinase-deficient patients from central Europe with hereditary hemolytic anemia. Blood. 1997 Mar 1;89(5):1793-9. van Solinge WW et al. Molecular modelling of human red blood cell pyruvate kinase: structural implications of a novel G1091 to a mutation causing severe nonspherocytic hemolytic anemia. Blood. 1997 Dec 15;90(12):4987-95. van Wijk R et al. Disruption of a novel regulatory element in the erythroid-specific promoter of the human PKLR gene causes severe pyruvate kinase deficiency. Blood. 2003 Feb 15;101(4):1596-602. Wang C et al. Human erythrocyte pyruvate kinase: characterization of the recombinant enzyme and a mutant form (R510Q) causing nonspherocytic hemolytic anemia. Blood. 2001 Nov 15;98(10):3113-20.
Mayo Clinic Laboratories, Mayo Clinic RCV000224660 SCV001713039 pathogenic not provided 2020-12-30 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
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000224660 SCV001930315 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000224660 SCV001958390 pathogenic not provided no assertion criteria provided clinical testing

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