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.
ClinVar Genomic variation as it relates to human health
NM_000298.6(PKLR):c.1529G>A (p.Arg510Gln)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(17)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
17
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000298.6(PKLR):c.1529G>A (p.Arg510Gln)
Variation ID: 1511 Accession: VCV000001511.41
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q22 1: 155291845 (GRCh38) [ NCBI UCSC ] 1: 155261636 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 20, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000298.6:c.1529G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000289.1:p.Arg510Gln missense NM_181871.4:c.1436G>A NP_870986.1:p.Arg479Gln missense NC_000001.11:g.155291845C>T NC_000001.10:g.155261636C>T NG_011677.1:g.14590G>A LRG_1136:g.14590G>A LRG_1136t1:c.1529G>A LRG_1136p1:p.Arg510Gln P30613:p.Arg510Gln - Protein change
- R510Q, R479Q
- Other names
- -
- Canonical SPDI
- NC_000001.11:155291844:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00036
Exome Aggregation Consortium (ExAC) 0.00040
Trans-Omics for Precision Medicine (TOPMed) 0.00048
The Genome Aggregation Database (gnomAD) 0.00052
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PKLR | - | - |
GRCh38 GRCh38 GRCh37 |
310 | 337 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2024 | RCV000001575.19 | |
| Pathogenic (12) |
criteria provided, multiple submitters, no conflicts
|
Jul 31, 2024 | RCV000224660.40 | |
|
PKLR-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 4, 2024 | RCV003421893.6 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 25, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280891.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
|
|
|
Pathogenic
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Pyruvate Kinase Deficiency
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000348594.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Sep 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000863295.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(May 15, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Pyruvate kinase deficiency
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001984862.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(May 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001156713.3
First in ClinVar: Feb 10, 2020 Last updated: Jan 08, 2022 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Sep 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329969.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(Jun 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018835.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Pyruvate kinase deficiency of red cells
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806768.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Oct 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713039.2
First in ClinVar: Jun 15, 2021 Last updated: Jun 02, 2024 |
Number of individuals with the variant: 36
|
|
|
Pathogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004025145.3
First in ClinVar: Aug 19, 2023 Last updated: Aug 04, 2024 |
|
|
|
Pathogenic
(May 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005050613.5
First in ClinVar: Jun 17, 2024 Last updated: Oct 20, 2024 |
Comment:
PKLR: PM3:Very Strong, PM1, PM2, PP4, PS3:Supporting
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003271819.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
|
|
|
Pathogenic
(Jul 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197173.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930315.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
Pathogenic
(Sep 04, 2024)
|
no assertion criteria provided
Method: clinical testing
|
PKLR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004117530.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Nov 15, 2001)
|
no assertion criteria provided
Method: literature only
|
ANEMIA, CONGENITAL, NONSPHEROCYTIC HEMOLYTIC, 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021731.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 20, 2024 |
Comment on evidence:
Baronciani and Beutler (1995) identified a 1529G-A transition in the PKLR gene, resulting in an arg510-to-gln (R510Q) substitution, as the most common mutation causing hemolytic … (more)
Baronciani and Beutler (1995) identified a 1529G-A transition in the PKLR gene, resulting in an arg510-to-gln (R510Q) substitution, as the most common mutation causing hemolytic anemia due to pyruvate kinase deficiency (CNSHA2; 266200) in Europeans. The authors found this mutation in 25 of 58 alleles that could be characterized in 30 unrelated patients with hereditary nonspherocytic hemolytic anemia with deficiency of pyruvate kinase by enzyme assay. With a single exception, this mutation was in linkage disequilibrium with 2 polymorphic markers, i.e., it was found with 1705C for the 1705A/C polymorphism and with 14 repeats in a microsatellite in intron 11. This finding was considered to be consistent with a single origin of this common mutation. Lenzner et al. (1997) found the 1529G-A mutation in 24 of 58 mutated alleles (45.3%) in 29 unrelated patients with PK deficiency in Central Europe. Nine patients were homozygous for the mutation; 6 were compound heterozygotes. They found that the mutation was more frequent among patients of German and English origin (14 of 18 patients were either homozygous or heterozygous) than among patients from Czechia/Slovakia (1 homozygote among 11 patients). Other mutations were found exclusively in the Czechia/Slovakia group and never among German and English patients. Nine patients homozygous for the 1529G-A mutation showed the same haplotype for 4 markers. However, the hematologic and clinical findings in these patients were different. Clinical symptoms ranged from a mild compensated hemolysis to intermediate anemia and severe anemia. All showed low residual enzyme activity between approximately 10 and 25% of normal, of which the more severe cases had lower PK activities than the milder forms. Reticulocyte counts varied between approximately 5 and 8% in the slightly affected patients to 25 to 66% in the seriously affected patients. The severely affected patients were characterized by a compensatory persistence of the M2-type enzyme in red cells, which accounted for about half of the residual PK activity. Wang et al. (2001) studied the mutant R510Q protein. Functional expression studies showed that the mutant protein retained its binding capacity to, and could be activated by, fructose 1,6-bisphosphate, and showed similar kinetics toward phosphoenolpyruvate and adenosine diphosphate as the wildtype enzyme. Conversely, the mutant protein had a dramatically decreased stability toward heat and was more susceptible to ATP inhibition. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958390.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
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Comment:
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
PKLR: PM3:Very Strong, PM1, PM2, PP4, PS3:Supporting
Comment:
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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
PKLR: PM3:Very Strong, PM1, PM2, PP4, PS3:Supporting
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias. | Russo R | American journal of hematology | 2018 | PMID: 29396846 |
| Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population. | van Bruggen R | PloS one | 2015 | PMID: 26658699 |
| Erythrocyte pyruvate kinase deficiency in an old-order Amish cohort: longitudinal risk and disease management. | Rider NL | American journal of hematology | 2011 | PMID: 21815188 |
| Pyruvate kinase deficiency in a South African kindred caused by a 1529A mutation in the PK-LR gene. | Durand PM | South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde | 2008 | PMID: 18683378 |
| Pyruvate kinase deficiency: the genotype-phenotype association. | Zanella A | Blood reviews | 2007 | PMID: 17360088 |
| Disruption of a novel regulatory element in the erythroid-specific promoter of the human PKLR gene causes severe pyruvate kinase deficiency. | van Wijk R | Blood | 2003 | PMID: 12393511 |
| Human erythrocyte pyruvate kinase: characterization of the recombinant enzyme and a mutant form (R510Q) causing nonspherocytic hemolytic anemia. | Wang C | Blood | 2001 | PMID: 11698298 |
| Molecular modelling of human red blood cell pyruvate kinase: structural implications of a novel G1091 to a mutation causing severe nonspherocytic hemolytic anemia. | van Solinge WW | Blood | 1997 | PMID: 9389718 |
| Molecular analysis of 29 pyruvate kinase-deficient patients from central Europe with hereditary hemolytic anemia. | Lenzner C | Blood | 1997 | PMID: 9057665 |
| Molecular study of pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia. | Baronciani L | The Journal of clinical investigation | 1995 | PMID: 7706479 |
| Mutations in the pyruvate kinase L gene in patients with hereditary hemolytic anemia. | Lenzner C | Blood | 1994 | PMID: 8180378 |
| Analysis of pyruvate kinase-deficiency mutations that produce nonspherocytic hemolytic anemia. | Baronciani L | Proceedings of the National Academy of Sciences of the United States of America | 1993 | PMID: 8483951 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKLR | - | - | - | - |
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Text-mined citations for rs113403872 ...
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Record last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.