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

gnomAD frequency: 0.00052  dbSNP: rs113403872

Total submissions: 14

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	2022-09-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the R510Q protein has decreased stability toward heat and is more susceptible to ATP inhibition, leading to enzyme instability and decreased enzyme levels in the cell (Wang et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29610156, 27432187, 27354418, 34662886, 11698298, 18683378, 8483951, 9057665, 29396846, 28760888, 31980526, 32273473, 33193643, 31589614, 33631127)
Illumina Laboratory Services, 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.
Eurofins Ntd Llc (ga)	RCV000224660	SCV000863295	pathogenic	not provided	2018-09-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224660	SCV001156713	pathogenic	not provided	2021-05-06	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
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000001575	SCV001984862	pathogenic	Pyruvate kinase deficiency of red cells	2020-05-15	criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous and a homozygous change in patients with (PMID: 8483951, 29396846). Functional studies on blood samples from individuals carrying this variant in the compound heterozygous and homozygous state demonstrate reduced pyruvate kinase activity (PMID: 8483951). In vitro studies of the mutant protein reveal that it is unstable and susceptible to ATP inhibition (PMID: 11698298). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.038% (108/282852) and thus is presumed to be rare. The c.1529G>A (p.Arg510Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1529G>A (p.Arg510Gln) variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000224660	SCV002018835	pathogenic	not provided	2023-06-23	criteria provided, single submitter	clinical testing
Invitae	RCV000224660	SCV003271819	pathogenic	not provided	2024-01-25	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 510 of the PKLR protein (p.Arg510Gln). This variant is present in population databases (rs113403872, gnomAD 0.07%). This missense change has been observed in individual(s) with pyruvate kinase deficiency (PMID: 8483951, 11698298, 18683378, 29396846). ClinVar contains an entry for this variant (Variation ID: 1511). 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 expected to disrupt PKLR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PKLR function (PMID: 11698298). For these reasons, this variant has been classified as Pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000224660	SCV004025145	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003421893	SCV004117530	pathogenic	PKLR-related condition	2023-12-06	criteria provided, single submitter	clinical testing	The PKLR c.1529G>A variant is predicted to result in the amino acid substitution p.Arg510Gln. This variant has previously been reported to be causative for pyruvate kinase deficiency (Baronciani and Beutler. 1993. PubMed ID: 8483951; Wang et al. 2001. PubMed ID: 11698298). This variant is reported in 0.075% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000224660	SCV001958390	pathogenic	not provided		no assertion criteria provided	clinical testing