chr1-155291845-C-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_000298.6(PKLR):c.1529G>A(p.Arg510Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000768 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000298.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKLR | ENST00000342741.6 | c.1529G>A | p.Arg510Gln | missense_variant | Exon 10 of 11 | 1 | NM_000298.6 | ENSP00000339933.4 | ||
PKLR | ENST00000392414.7 | c.1436G>A | p.Arg479Gln | missense_variant | Exon 10 of 11 | 1 | ENSP00000376214.3 |
Frequencies
GnomAD3 genomes AF: 0.000513 AC: 78AN: 152136Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000358 AC: 90AN: 251478Hom.: 0 AF XY: 0.000294 AC XY: 40AN XY: 135916
GnomAD4 exome AF: 0.000795 AC: 1162AN: 1461800Hom.: 0 Cov.: 33 AF XY: 0.000714 AC XY: 519AN XY: 727206
GnomAD4 genome AF: 0.000512 AC: 78AN: 152254Hom.: 0 Cov.: 31 AF XY: 0.000416 AC XY: 31AN XY: 74450
ClinVar
Submissions by phenotype
not provided Pathogenic:12
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The PKLR c.1529G>A; p.Arg510Gln variant (rs113403872, ClinVar Variation ID: 1511) is reported in both the homozygous and compound heterozygous state in multiple individuals affected with pyruvate kinase (PK) deficiency and is considered to be the most common cause of PK deficiency in European populations (Baronciani 1993, Baronciani 1995, Bianchi 2020, Christensen 2016, Durand 2008, Hou 2020, Jensen 2020, Lenzner 1997, Maciak 2020, Maciak 2024, Russo 2018, van Solinge 1997, van Wijk 2003). This variant is found in the general population with an overall allele frequency of 0.04% (108/282,852 alleles) in the Genome Aggregation Database (v2.1.1). Functional analyses of the variant protein show decreased thermostability, accelerated intracellular proteolytic degradation, and increased susceptibility to ATP inhibition (Lenzner 1997, Wang 2001). Computational analyses predict that this variant is deleterious (REVEL: 0.947). Based on available information, this variant is considered to be pathogenic. References: Baronciani L et al. Analysis of pyruvate kinase-deficiency mutations that produce nonspherocytic hemolytic anemia. Proc Natl Acad Sci U S A. 1993 May 1. PMID: 8483951. Baronciani L et al. Molecular study of pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia. J Clin Invest. 1995 Apr. PMID: 7706479. Bianchi P et al. Genotype-phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency. Am J Hematol. 2020 May. PMID: 32043619. Christensen RD et al. Siblings with severe pyruvate kinase deficiency and a complex genotype. Am J Med Genet A. 2016 Sep. PMID: 27354418. Durand PM et al. Pyruvate kinase deficiency in a South African kindred caused by a 1529A mutation in the PK-LR gene. S Afr Med J. 2008 Jun. PMID: 18683378. Hou YC et al. Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. Proc Natl Acad Sci U S A. 2020 Feb 11. PMID: 31980526. Jensen RFG et al. Erythrocytapheresis as a novel treatment option for adult patients with pyruvate kinase deficiency. Haematologica. 2020 Jul. PMID: 32273473. Lenzner C et al. Molecular analysis of 29 pyruvate kinase-deficient patients from central Europe with hereditary hemolytic anemia. Blood. 1997 Mar 1. PMID: 9057665. Maciak K et al. A Family Affected by a Life-Threatening Erythrocyte Defect Caused by Pyruvate Kinase Deficiency With Normal Iron Status: A Case Report. Front Genet. 2020 PMID: 33193643. Maciak K et al. PKLR mutations in pyruvate kinase deficient Polish patients: Functional characteristics of c.101-1G > A and c.1058delAAG variants. Blood Cells Mol Dis. 2024 Jul;107:102841. PMID: 38581917. Russo R et al. Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias. Am J Hematol. 2018 May. PMID: 29396846. 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. PMID: 9389718. 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. PMID: 12393511. 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. PMID: 11698298. -
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PKLR: PM3:Very Strong, PM1, PM2, PP4, PS3:Supporting -
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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) -
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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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
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Pyruvate kinase deficiency of red cells Pathogenic:4
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. -
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. -
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PKLR-related disorder Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at