MDH2
protein-codingmalate dehydrogenase 2
Gene summary
Malate dehydrogenase catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the citric acid cycle. The protein encoded by this gene is localized to the mitochondria and may play pivotal roles in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria. Several transcript variants encoding different isoforms 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 ~19.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0015025
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0015025
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0017366
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0015025
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0015025
Submitter: G2P
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MDH2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005918.4. 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 | 2 | 214 | 3 | 219 | ||
| missense | 1 | 6 | 369 | 12 | 388 | |
| nonsense | 1 | 1 | 1 | 3 | ||
| start loss | 2 | 2 | ||||
| frameshift | 7 | 2 | 3 | 12 | ||
| splice donor/acceptor (+/-2bp) | 1 | 6 | 4 | 11 | ||
| Total | 10 | 15 | 381 | 226 | 3 | 635 |
Highest pathogenic variant AF is 0.00018092146
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005909.2 | 9 | MANE Select | |
| Ensembl | ENSP00000327070.5 | 9 | MANE Select | |
| RefSeq | NP_001269332.1 | 8 | Standard | |
| RefSeq | NP_001269333.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Citrate cycle (TCA cycle) - Homo sapiens (human)
- Pyruvate metabolism - Homo sapiens (human)
- Cysteine and methionine metabolism - Homo sapiens (human)
- Glyoxylate and dicarboxylate metabolism - Homo sapiens (human)
- The oncogenic action of Succinate
Biological Process
- gluconeogenesis
- tricarboxylic acid cycle
- oxaloacetate metabolic process
- malate metabolic process
- internal protein amino acid acetylation
Molecular Function
- RNA binding
- L-malate dehydrogenase activity
- protein self-association
- malate dehydrogenase (NADP+) activity
Cellular Component
- nucleus
- mitochondrion
- mitochondrial matrix
- membrane
- myelin sheath
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000315758
- Coding exons
- 9
- Length
- 19458
- Individuals with no LoFs
- 125713
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 35
- Defined
- 125748
- p
- 0.000139
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0254 | 208 | 209 | 0.995 | 0.0000125 | 2148 |
| Missense (PolyPhen) | 67 | 77.941 | 0.85962 | 795 | ||
| Synonymous | -0.521 | 101 | 94.6 | 1.07 | 0.00000666 | 712 |
| Loss of Function | 2.10 | 6 | 14.7 | 0.409 | 6.88e-7 | 176 |
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 | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00026 | 0.00025 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Disease
- DISEASE: Epileptic encephalopathy, early infantile, 51 (EIEE51) [MIM:617339]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE51 is an autosomal recessive form characterized by onset of intractable seizures and hypotonia in the first days or weeks of life, and severely delayed psychomotor development. {ECO:0000269|PubMed:27989324}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.905
Intolerance Scores
- LoFtool
- 0.368
- RVIS EVS
- -0.33
- RVIS percentile EVS
- 30.7
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.998
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |