IDH1
protein-codingisocitrate dehydrogenase (NADP(+)) 1, the group of Isocitrate dehydrogenases
Gene summary
Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~29.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013808
Submitter: Ambry Genetics
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IDH1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005896.4. 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 | 1 | 158 | 159 | |||
| missense | 2 | 4 | 284 | 6 | 2 | 298 |
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 6 | 6 | ||||
| Total | 2 | 4 | 293 | 164 | 2 | 465 |
Highest pathogenic variant AF is 0.00039158878
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005887.2 | 8 | MANE Select | |
| Ensembl | ENSP00000260985.2 | 8 | MANE Select | |
| RefSeq | NP_001269315.1 | 8 | Standard | |
| RefSeq | NP_001269316.1 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| idh1 | Danio rerio | Structure: whole organism Quality: has fewer parts of type abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Citrate cycle (TCA cycle) - Homo sapiens (human)
- Central carbon metabolism in cancer - Homo sapiens (human)
- Glutathione metabolism - Homo sapiens (human)
- Peroxisome - Homo sapiens (human)
- Warburg Effect
Biological Process
- glyoxylate cycle
- tricarboxylic acid cycle
- isocitrate metabolic process
- 2-oxoglutarate metabolic process
- protein targeting to peroxisome
Molecular Function
- magnesium ion binding
- isocitrate dehydrogenase (NADP+) activity
- signaling receptor binding
- identical protein binding
- protein homodimerization activity
Cellular Component
- extracellular region
- cytoplasm
- mitochondrion
- peroxisome
- peroxisomal matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000415913
- Coding exons
- 8
- Length
- 29848
- Individuals with no LoFs
- 125703
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 45
- Defined
- 125748
- p
- 0.000179
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.604 | 207 | 233 | 0.889 | 0.0000124 | 2754 |
| Missense (PolyPhen) | 87 | 106.08 | 0.82011 | 1272 | ||
| Synonymous | 0.873 | 72 | 82.1 | 0.877 | 0.00000486 | 757 |
| Loss of Function | 0.404 | 19 | 21.0 | 0.905 | 0.00000109 | 248 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00032 | 0.00031 | rare |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00018 | 0.00018 | rare |
| South Asian | 0.00029 | 0.00029 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Disease
- DISEASE: Glioma (GLM) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:19117336, ECO:0000269|PubMed:19935646}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2- hydroxyglutarate are correlated with an elevated risk of malignant brain tumors. {ECO:0000269|PubMed:19935646}.; DISEASE: Note=Genetic variations are associated with cartilaginous tumors such as enchondroma or chondrosarcoma. Mutations of Arg-132 to Cys, Gly or His abolish the conversion of isocitrate to alpha- ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)- 2-hydroxyglutarate. {ECO:0000269|PubMed:26161668}.;
Recessive Scores
- pRec
- 0.416
Intolerance Scores
- LoFtool
- 0.568
- RVIS EVS
- 0.02
- RVIS percentile EVS
- 55.45
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.915
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |