MCEE
protein-codingmethylmalonyl-CoA epimerase, the group of Glyoxalase domain containing family
Gene summary
The product of this gene catalyzes the interconversion of D- and L-methylmalonyl-CoA during the degradation of branched chain amino acids. odd chain-length fatty acids, and other metabolites. Mutations in this gene result in methylmalonyl-CoA epimerase deficiency, which is presented as mild to moderate methylmalonic aciduria. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~20.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009615
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009615
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009615
Submitter: ClinGen
MCEE, which encodes methylmalonyl-CoA epimerase, was first reported in relation to autosomal recessive methylmalonyl-CoA epimerase deficiency in 2006 (Chandler et al, PMID: 16843692 AND Dobson et al, PMID: 16697227). The primary phenotype observed in probands is methylmalonic aciduria, with occasional metabolic acidosis or other phenotypes following febrile infections. Only four unique variants (e.g. missense, deep intronic, nonsense) have been reported in humans, with the founder null variant Arg47Ter in the predominance of cases. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in less than twenty probands mostly of European ancestry (PMIDs: 16697227, 17823972, 27699154, 29104221, 30682498, 31146325). These probands display various phenotypes, however the range from asymptomatic to neurodevelopmental phenotypes makes causation of any phenotype other than the methylmalonic aciduria uncertain. The mechanism for disease is biallelic loss of function, with defective protein activity causing a blockage in the propionyl-CoA to succinyl-CoA pathway in human cells and a resulting buildup of methylmalonic acid. This is also observed in other genes that encode in the similar pathway, such as MMUT, MMAA, MMAB, and MMADHC. This gene-disease association is also supported by biochemical function and functional alteration data. MCEE's place in the pathway and the predicted result of a blockage provides significant evidence towards the pathogenicity. In two different cell lines, HeLa cells and C. elegans nematodes, disruption of the MCEE gene led to a direct decrease in 1-[14C]-propionate incorporation and a resulting buildup of methylmalonic acid. In summary, MCEE is definitively associated with autosomal recessive methylmalonyl-CoA epimerase deficiency.This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0009615
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic; Ophthalmologic
Intervention: Biochemical
Rationale: Long-term dietary (high-calorie diet low in propiogenic amino acid precursors with carnitine supplementation) and medical management (eg, IM hydroxocobalamin, antibiotics to decrease propionate production) is indicated; Fasting and high-protein consumption should be avoided; In the emergent setting, prompt recognition and appropriate metabolic care may be beneficial to decrease morbidity and mortality; Antioxidants for optic nerve atrophy may be beneficial; Liver/kidney transplant has been described in methylmalonic acidemia
Comments: No response to vitamin B12 administration was documented in the affected individual
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MCEE variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_032601.4. 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 | 45 | 45 | ||||
| missense | 38 | 4 | 1 | 43 | ||
| nonsense | 1 | 1 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 2 | 5 | |||
| splice donor/acceptor (+/-2bp) | 3 | 1 | 4 | |||
| Total | 4 | 3 | 42 | 49 | 1 | 99 |
Highest pathogenic variant AF is 0.00044425222
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_115990.3 | 3 | MANE Select | |
| Ensembl | ENSP00000244217.5 | 3 | MANE Select | |
| Ensembl | ENSP00000391140.1 | 2 | Standard | |
| Ensembl | ENSP00000441569.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Propanoate metabolism - Homo sapiens (human)
- Valine, leucine and isoleucine degradation - Homo sapiens (human)
- Glyoxylate and dicarboxylate metabolism - Homo sapiens (human)
- 3-Methylglutaconic Aciduria Type I
- Valine, Leucine and Isoleucine Degradation
Biological Process
- short-chain fatty acid catabolic process
- L-methylmalonyl-CoA metabolic process
Molecular Function
- methylmalonyl-CoA epimerase activity
- protein binding
- metal ion binding
Cellular Component
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000244217
- Coding exons
- 3
- Length
- 20556
- Individuals with no LoFs
- 125665
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 81
- Defined
- 125746
- p
- 0.000322
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.519 | 79 | 93.1 | 0.849 | 0.00000434 | 1127 |
| Missense (PolyPhen) | 21 | 30.449 | 0.68969 | 409 | ||
| Synonymous | 0.855 | 29 | 35.5 | 0.817 | 0.00000170 | 371 |
| Loss of Function | 1.05 | 3 | 5.69 | 0.527 | 3.06e-7 | 69 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000057 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00058 | 0.00056 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Disease
- DISEASE: Methylmalonyl-CoA epimerase deficiency (MCEED) [MIM:251120]: Autosomal recessive inborn error of amino acid metabolism, involving valine, threonine, isoleucine and methionine. This organic aciduria may present in the neonatal period with life-threatening metabolic acidosis, hyperammonemia, feeding difficulties, pancytopenia and coma. {ECO:0000269|PubMed:16752391}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.161
Intolerance Scores
- LoFtool
- 0.678
- RVIS EVS
- 0.68
- RVIS percentile EVS
- 84.93
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.786
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |