PCK1

phosphoenolpyruvate carboxykinase 1

Basic information

Region (hg38): 20:57561079-57568121

Links

ENSG00000124253 ∙ NCBI:5105 ∙ OMIM:614168 ∙ HGNC:8724 ∙ Uniprot:P35558 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• phosphoenolpyruvate carboxykinase deficiency (Supportive), mode of inheritance: AR
• phosphoenolpyruvate carboxykinase deficiency, cytosolic (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Phosphoenolpyruvate carboxykinase-1 deficiency, cytosolic	AR	Biochemical	Individuals have been described with manifestations such as early-onset hypoglycemia, and awareness can allow prompt treatment of acute episodes as well as longer-term dietary management (low-fat, high-carbohydrate diet with frequent feedings)	Biochemical	24863970; 26971250; 28216384

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PCK1 gene.

• not provided (144 variants)
• Phosphoenolpyruvate carboxykinase deficiency, cytosolic (81 variants)
• Inborn genetic diseases (37 variants)
• Phosphoenolpyruvate carboxykinase (GTP) deficiency (13 variants)
• PCK1-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PCK1 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			4	33	12	49
missense			83	5	5	93
nonsense	1		1			2
start loss						0
frameshift			1			1
inframe indel			2			2
splice donor/acceptor (+/-2bp)		1	1			2
splice region			2	5		7
non coding			27	8	14	49
Total	1	1	119	46	31

Variants in PCK1

This is a list of pathogenic ClinVar variants found in the PCK1 region.

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

Position	Type	Phenotype	Significance	ClinVar
20-57561180-C-T		Phosphoenolpyruvate carboxykinase deficiency, cytosolic	Uncertain significance (Jan 13, 2018)
20-57561190-C-T		Phosphoenolpyruvate carboxykinase deficiency, cytosolic	Uncertain significance (Jan 12, 2018)
20-57561358-G-A		Phosphoenolpyruvate carboxykinase deficiency, cytosolic	Uncertain significance (Jan 13, 2018)
20-57561360-T-C		Phosphoenolpyruvate carboxykinase deficiency, cytosolic	Uncertain significance (Jan 13, 2018)
20-57561409-G-A		Phosphoenolpyruvate carboxykinase deficiency, cytosolic	Uncertain significance (Jan 13, 2018)
20-57561418-C-T		Phosphoenolpyruvate carboxykinase deficiency, cytosolic • PCK1-related disorder	Conflicting classifications of pathogenicity (Jan 15, 2024)
20-57561423-G-A		Phosphoenolpyruvate carboxykinase deficiency, cytosolic	Benign (Jan 19, 2024)
20-57561432-C-T			Likely benign (Dec 15, 2021)
20-57561433-G-A		Inborn genetic diseases	Uncertain significance (Mar 06, 2023)
20-57561442-C-T		Inborn genetic diseases	Likely benign (Feb 13, 2024)
20-57561446-C-T			Likely benign (Oct 24, 2022)
20-57561454-G-T			Benign (Jan 28, 2022)
20-57561475-A-G		Phosphoenolpyruvate carboxykinase deficiency, cytosolic • Inborn genetic diseases	Uncertain significance (Aug 04, 2023)
20-57561480-A-G		Phosphoenolpyruvate carboxykinase deficiency, cytosolic	Benign (Jan 31, 2024)
20-57561495-G-A			Likely benign (Apr 06, 2022)
20-57561505-G-A		Inborn genetic diseases	Uncertain significance (Jan 29, 2024)
20-57561513-C-T		Phosphoenolpyruvate carboxykinase deficiency, cytosolic	Conflicting classifications of pathogenicity (Dec 28, 2023)
20-57561522-G-A			Likely benign (Oct 11, 2023)
20-57561542-A-G		Inborn genetic diseases	Uncertain significance (Sep 24, 2021)
20-57561545-T-C		Phosphoenolpyruvate carboxykinase deficiency, cytosolic	Uncertain significance (Sep 07, 2018)
20-57561552-C-T		Phosphoenolpyruvate carboxykinase deficiency, cytosolic	Conflicting classifications of pathogenicity (Feb 01, 2024)
20-57561558-TGAG-T		PCK1-related disorder	Uncertain significance (Feb 12, 2023)
20-57561562-G-A			Uncertain significance (Jun 25, 2023)
20-57561574-C-T			Uncertain significance (Jan 02, 2020)
20-57561575-G-A			Uncertain significance (Aug 22, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PCK1	protein_coding	protein_coding	ENST00000319441	9	5378

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.75e-15	0.0358	125666	0	82	125748	0.000326

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0430	386	384	1.01	0.0000227	4114
Missense in Polyphen		165	180.31	0.91511		1846
Synonymous	-1.28	182	161	1.13	0.0000111	1192
Loss of Function	0.427	23	25.3	0.909	0.00000108	296

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000621	0.000621
Ashkenazi Jewish	0.000104	0.0000992
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.000433	0.000431
Middle Eastern	0.0000544	0.0000544
South Asian	0.000434	0.000425
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP), the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors derived from the citric acid cycle. {ECO:0000269|PubMed:24863970, ECO:0000269|PubMed:26971250, ECO:0000269|PubMed:28216384}.
• Disease: DISEASE: Phosphoenolpyruvate carboxykinase deficiency, cytosolic (PCKDC) [MIM:261680]: An autosomal recessive metabolic disorder characterized by impaired gluconeogenesis, hypoglycemia, hypotonia, hepatomegaly, hepatic dysfunction, failure to thrive, lactic acidosis, and elevated tricarboxylic acid intermediates, particularly fumarate, in urine. {ECO:0000269|PubMed:24863970, ECO:0000269|PubMed:26971250, ECO:0000269|PubMed:28216384}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);Citrate cycle (TCA cycle) - Homo sapiens (human);Pyruvate metabolism - Homo sapiens (human);Adipocytokine signaling pathway - Homo sapiens (human);Glycolysis / Gluconeogenesis - Homo sapiens (human);Insulin resistance - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);Proximal tubule bicarbonate reclamation - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Glucagon signaling pathway - Homo sapiens (human);PPAR signaling pathway - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Abacavir Pathway, Pharmacokinetics/Pharmacodynamics;Pyruvate Dehydrogenase Complex Deficiency;Primary hyperoxaluria II, PH2;Pyruvate kinase deficiency;Gluconeogenesis;Leigh Syndrome;Glycogenosis, Type IA. Von gierke disease;Glycogenosis, Type IC;Glycogen Storage Disease Type 1A (GSD1A) or Von Gierke Disease;Pyruvate Metabolism;Pyruvate Decarboxylase E1 Component Deficiency (PDHE1 Deficiency);Triosephosphate isomerase;Fructose-1,6-diphosphatase deficiency;Phosphoenolpyruvate carboxykinase deficiency 1 (PEPCK1);Glycogenosis, Type IB;Transcriptional regulation of white adipocyte differentiation;Adipogenesis;TCA Cycle and Deficiency of Pyruvate Dehydrogenase complex (PDHc);Estrogen Receptor Pathway;Nuclear Receptors Meta-Pathway;Angiopoietin Like Protein 8 Regulatory Pathway;Amino Acid metabolism;PPAR signaling pathway;PI3K-Akt Signaling Pathway;Glycolysis and Gluconeogenesis;Metabolism of carbohydrates;Citrate cycle;Glycolysis and Gluconeogenesis;Abacavir metabolism;Abacavir transport and metabolism;Metabolism;TCA cycle;gluconeogenesis;Gluconeogenesis;Glucose metabolism;FOXA2 and FOXA3 transcription factor networks (Consensus)

Recessive Scores

• pRec: 0.502

Intolerance Scores

• loftool: 0.718
• rvis_EVS: 0.28
• rvis_percentile_EVS: 70.76

Haploinsufficiency Scores

• pHI: 0.532
• hipred: Y
• hipred_score: 0.532
• ghis: 0.459

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.999

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pck1
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary 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); growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: pck1
• Affected structure: glucose homeostasis
• Phenotype tag: abnormal
• Phenotype quality: process quality

Gene ontology

• Biological process: glucose metabolic process;pyruvate metabolic process;gluconeogenesis;oxaloacetate metabolic process;internal protein amino acid acetylation;aging;response to activity;propionate catabolic process;response to lipopolysaccharide;response to insulin;cellular response to insulin stimulus;response to lipid;glucose homeostasis;response to starvation;glycerol biosynthetic process from pyruvate;cellular response to potassium ion starvation;positive regulation of transcription from RNA polymerase II promoter in response to acidic pH;hepatocyte differentiation;response to interleukin-6;cellular response to retinoic acid;cellular response to cAMP;cellular response to fructose stimulus;cellular response to glucose stimulus;cellular response to interleukin-1;cellular response to tumor necrosis factor;cellular response to glucagon stimulus;cellular response to hypoxia;cellular response to dexamethasone stimulus;response to methionine
• Cellular component: cytoplasm;mitochondrion;cytosol;extracellular exosome
• Molecular function: magnesium ion binding;phosphoenolpyruvate carboxykinase (GTP) activity;GTP binding;GDP binding;manganese ion binding;carboxylic acid binding