PKLR

protein-coding

pyruvate kinase L/R

Gene summary

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]

MANE transcript

NM_000298.6

Inheritance

AR, AD

ClinVar variants

P:153U:207B:36

Top phenotype

Anemia, congenital, nonspherocytic hemolytic, 2

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr1:155,289,293-155,301,438

External References & Databases

Ensembl (ENSG00000143627)

Transcript & Mutation Effects

hg38 • Region Span ~12.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pyruvate kinase deficiency of red cellsDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009950

Submitter: ClinGen

PKLR was first reported in relation to autosomal recessive pyruvate kinase deficiency (PKD)/anemia in 1991 (Kanno et al., PMID: 1896471). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found distinct differences in molecular mechanism, inheritance pattern, and phenotype. Therefore, the following disease entities have been split into multiple disease entities: autosomal recessive pyruvate kinase deficiency and autosomal dominant pyruvate kinase hyperactivity. Due to very limited evidence, a curation for autosomal dominant pyruvate kinase hyperactivity was deemed unnecessary. At least 19 variants (missense, in-frame deletion, splicing, and nonsense) that have been reported in more than 20 probands in 4 publications are included in this curation (PMID: 1896471, 9057665, 9827908, 16704447). While a wide array of mutations are linked to disease, there are three recurrent mutations seen in affected patients (two missense and one nonsense). This gene-disease relationship is also supported by experimental evidence (expression, functional alteration, and a mouse model; PMID: 1896471, 17466543, 11960989). Prenatal anemia can present with hydrops fetalis or fetal demise. Confirmation of anemia and PKD deficiency is possible via umbilical blood vessel sampling and amniocentesis. Neonatal diagnosis of jaundice/anemia is also possible. The mechanism of pathogenicity is reported to be loss-of-function. In summary, there is definitive evidence supporting the relationship between PKLR and autosomal recessive PKD. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Prenatal GCEP on the meeting date 2/07/2024 (SOP Version 10).

pyruvate kinase hyperactivityLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007067

Submitter: Labcorp Genetics (formerly Invitae)

pyruvate kinase deficiency of red cellsSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009950

Submitter: Orphanet

pyruvate kinase deficiency of red cellsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009950

Submitter: Labcorp Genetics (formerly Invitae)

pyruvate kinase deficiency of red cellsDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009950

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

pyruvate kinase deficiency of red cellsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009950

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Anemia, congenital, nonspherocytic hemolytic, 2AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: In some individuals, due to severe anemia, RBC transfusion and/or splenectomy may be beneficial

Refs: 13924348; 13919474; 14014643; 14255553; 14300761; 4160306; 5940199; 7426754; 1896471; 1536957; 8285758; 7949104; 7706479; 8161798; 8807089; 8664896; 8579052; 8616073; 9090535; 9057665; 9160692; 9657767; 9886305; 10772876; 9827908; 12393511; 15491302; 15953013; 15982340; 16704447; 18420493; 18759866; 19085939; 19743919; 23082140

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PKLR variants in ClinVar

12 Conditions Cataloged

not providedTotal: 322

Pyruvate kinase deficiency of red cellsTotal: 126

PKLR-related disorderTotal: 59

Inborn genetic diseasesTotal: 50

not specifiedTotal: 29

Pyruvate kinase hyperactivityTotal: 20

Congenital anemiaTotal: 2

Fetal anomalies with a likely genetic causeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000298.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar	1 clinvar	4 clinvar	34 clinvar		40
missense	9 clinvar	81 clinvar	201 clinvar	2 clinvar		293
nonsense	10 clinvar	8 clinvar	1 clinvar			19
start loss						0
frameshift	18 clinvar	7 clinvar				25
splice donor/acceptor (+/-2bp)	9 clinvar	9 clinvar	1 clinvar			19
Total	47	106	207	36	0	396

Highest pathogenic variant AF is 0.002953937

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000298.6	RefSeq	NP_000289.1	11	MANE Select
ENST00000342741.6	Ensembl	ENSP00000339933.4	11	MANE Select
NM_181871.4	RefSeq	NP_870986.1	11	Standard
ENST00000392414.7	Ensembl	ENSP00000376214.3	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pyruvate metabolism - Homo sapiens (human)
Glycolysis / Gluconeogenesis - Homo sapiens (human)
Type II diabetes mellitus - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Maturity onset diabetes of the young - Homo sapiens (human)

Biological Process

response to hypoxia
glycolytic process
response to heat
response to glucose
response to lithium ion

Molecular Function

magnesium ion binding
pyruvate kinase activity
ATP binding
kinase activity
potassium ion binding

Cellular Component

cytoplasm
cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000342741
Coding exons: 11
Length: 11596
Individuals with no LoFs: 125692
Homozygous LoFs: 0
Heterozygous LoFs: 56
Defined: 125748
p: 0.000223

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.981	310	363	0.855	0.0000245	3661
Missense (PolyPhen)		135	170.32	0.79263		1756
Synonymous	-0.230	149	145	1.02	0.00000942	1269
Loss of Function	1.84	14	23.7	0.591	0.00000135	257

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00036	0.00030	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a key role in glycolysis. {ECO:0000250}.;
Disease: DISEASE: Pyruvate kinase hyperactivity (PKHYP) [MIM:102900]: Autosomal dominant phenotype characterized by increase of red blood cell ATP. {ECO:0000269|PubMed:9090535}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pyruvate kinase deficiency of red cells (PKRD) [MIM:266200]: A frequent cause of hereditary non-spherocytic hemolytic anemia. Clinically, pyruvate kinase-deficient patients suffer from a highly variable degree of chronic hemolysis, ranging from severe neonatal jaundice and fatal anemia at birth, severe transfusion-dependent chronic hemolysis, moderate hemolysis with exacerbation during infection, to a fully compensated hemolysis without apparent anemia. {ECO:0000269|PubMed:11328279, ECO:0000269|PubMed:11960989, ECO:0000269|PubMed:1536957, ECO:0000269|PubMed:1896471, ECO:0000269|PubMed:19085939, ECO:0000269|PubMed:2018831, ECO:0000269|PubMed:21794208, ECO:0000269|PubMed:7706479, ECO:0000269|PubMed:8161798, ECO:0000269|PubMed:8180378, ECO:0000269|PubMed:8476433, ECO:0000269|PubMed:8481523, ECO:0000269|PubMed:8483951, ECO:0000269|PubMed:9482576, ECO:0000269|PubMed:9827908, ECO:0000269|PubMed:9886305, ECO:0000269|Ref.24}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.756

Intolerance Scores

LoFtool: 0.0609
RVIS EVS: 0.0000761
RVIS percentile EVS: 53.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.00377

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium