PKLR

pyruvate kinase L/R

Basic information

Region (hg38): 1:155289292-155301438

Links

ENSG00000143627 ∙ NCBI:5313 ∙ OMIM:609712 ∙ HGNC:9020 ∙ Uniprot:P30613 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• pyruvate kinase hyperactivity (Limited), mode of inheritance: AD
• pyruvate kinase deficiency of red cells (Definitive), mode of inheritance: AR
• pyruvate kinase deficiency of red cells (Supportive), mode of inheritance: AR
• pyruvate kinase deficiency of red cells (Strong), mode of inheritance: AR
• pyruvate kinase deficiency of red cells (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pyruvate kinase deficiency of red cells	AR	Hematologic	In some individuals, due to severe anemia, RBC transfusion and/or splenectomy may be beneficial	Hematologic	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

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PKLR gene.

• not provided (195 variants)
• Pyruvate kinase deficiency of red cells (106 variants)
• not specified (15 variants)
• Inborn genetic diseases (10 variants)
• PKLR-related condition (9 variants)
• Pyruvate kinase hyperactivity (4 variants)
• Pyruvate kinase deficiency of red cells;Pyruvate kinase hyperactivity (3 variants)
• Pyruvate kinase hyperactivity;Pyruvate kinase deficiency of red cells (3 variants)
• Hemolytic anemia (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PKLR gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	9	1	15
missense	7	29	103			139
nonsense	9	3	1			13
start loss						0
frameshift	7	4				11
inframe indel		1	1			2
splice donor/acceptor (+/-2bp)	6	4				10
splice region		1	9	2		12
non coding		1	32	4	7	44
Total	29	42	142	13	8

Highest pathogenic variant AF is 0.000512

Variants in PKLR

This is a list of pathogenic ClinVar variants found in the PKLR region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-155289295-C-T		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 13, 2018)
1-155289467-C-T		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 12, 2018)
1-155289505-A-G		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 13, 2018)
1-155289531-G-A		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 12, 2018)
1-155289532-C-T		Pyruvate kinase deficiency of red cells	Benign (Jan 12, 2018)
1-155289679-A-C		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 12, 2018)
1-155289706-A-G		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 13, 2018)
1-155289793-G-T		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 12, 2018)
1-155289817-A-G		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 13, 2018)
1-155289837-T-C		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 12, 2018)
1-155289990-C-T		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 13, 2018)
1-155290072-G-A		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 13, 2018)
1-155290073-C-T		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 12, 2018)
1-155290216-A-G		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 13, 2018)
1-155290221-A-T		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 12, 2018)
1-155290223-GCCT-G		Pyruvate kinase deficiency of red cells	Uncertain significance (Jun 14, 2016)
1-155290230-G-A		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 13, 2018)
1-155290297-G-A		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 13, 2018)
1-155290305-G-A		Pyruvate kinase deficiency of red cells	Benign (Nov 12, 2018)
1-155290558-G-A		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 12, 2018)
1-155290558-G-C		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 13, 2018)
1-155290558-GA-TG			Uncertain significance (Jan 25, 2020)
1-155290559-A-C		Pyruvate kinase deficiency of red cells	Uncertain significance (Jan 12, 2018)
1-155290559-A-G		not specified • Pyruvate kinase deficiency of red cells	Benign (Aug 19, 2022)
1-155290591-C-T		Pyruvate kinase deficiency of red cells • not specified	Uncertain significance (Oct 15, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PKLR	protein_coding	protein_coding	ENST00000342741	11	11596

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.49e-7	0.941	125692	0	56	125748	0.000223

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.981	310	363	0.855	0.0000245	3661
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000571	0.000568
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.000357	0.000299
Middle Eastern	0.000163	0.000163
South Asian	0.000131	0.000131
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);Purine metabolism - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Abacavir Pathway, Pharmacokinetics/Pharmacodynamics;Warburg Effect;Pyruvate Dehydrogenase Complex Deficiency;Glycolysis;Glycogenosis, Type VII. Tarui disease;Primary hyperoxaluria II, PH2;Pyruvate kinase deficiency;Leigh Syndrome;Fanconi-bickel syndrome;Pyruvate Metabolism;Pyruvate Decarboxylase E1 Component Deficiency (PDHE1 Deficiency);Integrated Lung Cancer Pathway;Pathways in clear cell renal cell carcinoma;Glycolysis and Gluconeogenesis;chrebp regulation by carbohydrates and camp;Metabolism of carbohydrates;Citrate cycle;Folate metabolism;Alanine Aspartate Asparagine metabolism;Glycolysis Gluconeogenesis;Metabolism;Glycolysis;Purine nucleotides nucleosides metabolism;Pyruvate metabolism;glycolysis;superpathway of conversion of glucose to acetyl CoA and entry into the TCA cycle;Glucose metabolism;FOXA2 and FOXA3 transcription factor networks (Consensus)

Recessive Scores

• pRec: 0.756

Intolerance Scores

• loftool: 0.0609
• rvis_EVS: 0.0000761
• rvis_percentile_EVS: 53.98

Haploinsufficiency Scores

• pHI: 0.827
• hipred: Y
• hipred_score: 0.523
• ghis: 0.406

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.00377

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pklr
• Phenotype: immune system phenotype; homeostasis/metabolism phenotype; hematopoietic system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Gene ontology

• Biological process: response to hypoxia;glycolytic process;response to heat;response to glucose;response to lithium ion;cellular response to insulin stimulus;response to ATP;response to cAMP;canonical glycolysis;cellular response to epinephrine stimulus
• Cellular component: cytoplasm;cytosol;extracellular exosome
• Molecular function: magnesium ion binding;pyruvate kinase activity;ATP binding;kinase activity;potassium ion binding