PDP1
protein-codingpyruvate dehydrogenase phosphatase catalytic subunit 1, the group of Protein phosphatases, Mg2+/Mn2+ dependent
Gene summary
Pyruvate dehydrogenase (E1) is one of the three components (E1, E2, and E3) of the large pyruvate dehydrogenase complex. Pyruvate dehydrogenase kinases catalyze phosphorylation of serine residues of E1 to inactivate the E1 component and inhibit the complex. Pyruvate dehydrogenase phosphatases catalyze the dephosphorylation and activation of the E1 component to reverse the effects of pyruvate dehydrogenase kinases. Pyruvate dehydrogenase phosphatase is a heterodimer consisting of catalytic and regulatory subunits. Two catalytic subunits have been reported; one is predominantly expressed in skeletal muscle and another one is is much more abundant in the liver. The catalytic subunit, encoded by this gene, is the former, and belongs to the protein phosphatase 2C (PP2C) superfamily. Along with the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinases, this enzyme is located in the mitochondrial matrix. Mutation in this gene causes pyruvate dehydrogenase phosphatase deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Jun 2009]
- PPM2C
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~68.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012120
Submitter: Orphanet
Inheritance Pattern: Unknown
Disease ID:MONDO:0007661
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012120
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012120
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012120
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012120
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: As with other conditions that involve seizures, optimal seizure control is important, and may be influenced by knowing the molecular cause
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PDP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018444.4. 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 | 76 | 76 | ||||
| missense | 96 | 4 | 100 | |||
| nonsense | 1 | 1 | 3 | 5 | ||
| start loss | 0 | |||||
| frameshift | 5 | 1 | 6 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 6 | 100 | 80 | 0 | 187 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060914.2 | 1 | MANE Select | |
| Ensembl | ENSP00000297598.4 | 1 | MANE Select | |
| RefSeq | NP_001155251.1 | 2 | Standard | |
| RefSeq | NP_001155252.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Regulation of pyruvate dehydrogenase (PDH) complex
- Pyruvate metabolism
- Pyruvate metabolism and Citric Acid (TCA) cycle
- The citric acid (TCA) cycle and respiratory electron transport
- Metabolism
Biological Process
- regulation of acetyl-CoA biosynthetic process from pyruvate
- peptidyl-threonine dephosphorylation
- positive regulation of pyruvate dehydrogenase activity
Molecular Function
- protein serine/threonine phosphatase activity
- magnesium-dependent protein serine/threonine phosphatase activity
- [pyruvate dehydrogenase (lipoamide)] phosphatase activity
- protein binding
- metal ion binding
Cellular Component
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000396200
- Coding exons
- 2
- Length
- 68260
- Individuals with no LoFs
- 125734
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 14
- Defined
- 125748
- p
- 0.0000557
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.62 | 220 | 299 | 0.736 | 0.0000159 | 3710 |
| Missense (PolyPhen) | 63 | 122.48 | 0.51437 | 1508 | ||
| Synonymous | -0.767 | 126 | 116 | 1.09 | 0.00000636 | 1115 |
| Loss of Function | 3.15 | 4 | 18.7 | 0.214 | 0.00000111 | 213 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000094 | 0.000092 | rare |
| European (Non-Finnish) | 0.000081 | 0.000079 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the dephosphorylation and concomitant reactivation of the alpha subunit of the E1 component of the pyruvate dehydrogenase complex. {ECO:0000250}.;
- Disease
- DISEASE: Pyruvate dehydrogenase phosphatase deficiency (PDP deficiency) [MIM:608782]: Results in lactic acidosis leading to neurological dysfunction. {ECO:0000269|PubMed:15855260}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.475
Intolerance Scores
- LoFtool
- 0.631
- RVIS EVS
- -0.76
- RVIS percentile EVS
- 13.33
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.499
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |