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

Genomes: 𝑓 0.00051 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00079 ( 0 hom. )

Consequence

PKLR
NM_000298.6 missense

Scores

11
6
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 7.75
Variant links:
Genes affected
PKLR (HGNC:9020): (pyruvate kinase L/R) The protein encoded by this gene is a pyruvate kinase that catalyzes the transphosphorylation of phohsphoenolpyruvate into pyruvate and ATP, which is the rate-limiting step of glycolysis. Defects in this enzyme, due to gene mutations or genetic variations, are the common cause of chronic hereditary nonspherocytic hemolytic anemia (CNSHA or HNSHA). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000298.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.798
PP5
Variant 1-155291845-C-T is Pathogenic according to our data. Variant chr1-155291845-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155291845-C-T is described in UniProt as null. Variant chr1-155291845-C-T is described in Lovd as [Pathogenic]. Variant chr1-155291845-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKLRNM_000298.6 linkc.1529G>A p.Arg510Gln missense_variant Exon 10 of 11 ENST00000342741.6 NP_000289.1 P30613-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKLRENST00000342741.6 linkc.1529G>A p.Arg510Gln missense_variant Exon 10 of 11 1 NM_000298.6 ENSP00000339933.4 P30613-1
PKLRENST00000392414.7 linkc.1436G>A p.Arg479Gln missense_variant Exon 10 of 11 1 ENSP00000376214.3 P30613-2

Frequencies

GnomAD3 genomes
AF:
0.000513
AC:
78
AN:
152136
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000290
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000956
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000358
AC:
90
AN:
251478
Hom.:
0
AF XY:
0.000294
AC XY:
40
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000738
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000795
AC:
1162
AN:
1461800
Hom.:
0
Cov.:
33
AF XY:
0.000714
AC XY:
519
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00102
Gnomad4 OTH exome
AF:
0.000381
GnomAD4 genome
AF:
0.000512
AC:
78
AN:
152254
Hom.:
0
Cov.:
31
AF XY:
0.000416
AC XY:
31
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000956
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000638
Hom.:
0
Bravo
AF:
0.000484
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000930
AC:
8
ExAC
AF:
0.000404
AC:
49
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000654
EpiControl
AF:
0.000652

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:12
Jun 25, 2014
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 25, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 23, 2023
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PKLR: PM3:Very Strong, PM1, PM2, PP4, PS3:Supporting -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 29, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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) -

Oct 18, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 06, 2018
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 25, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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). 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. -

Jul 13, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Pyruvate kinase deficiency of red cells Pathogenic:4
May 15, 2020
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Nov 15, 2001
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Mar 26, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

PKLR-related disorder Pathogenic:1
Sep 04, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.48
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.99
D;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.98
D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.80
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.7
D;D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.023
D;D
Sift4G
Uncertain
0.027
D;D
Polyphen
1.0
D;.
Vest4
0.92
MVP
1.0
MPC
1.4
ClinPred
0.60
D
GERP RS
4.8
Varity_R
0.95
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs113403872; hg19: chr1-155261636; COSMIC: COSV61362751; COSMIC: COSV61362751; API