GeneBe

MMACHC

protein-coding

metabolism of cobalamin associated C

Gene summary

The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]

MANE transcript

NM_015506.3

Inheritance

AR, Digenic

ClinVar variants

P:190U:155B:168

Top phenotype

Methylmalonic aciduria and homocystinuria, cblC type

gnomAD constraint

pLI —, LoF o/e 1.21

Max pathogenic AF

—

Genomic locus

chr1:45,500,300-45,513,382

External References & Databases

Ensembl (ENSG00000132763)NCBI Gene (25974)OMIM (609831)HGNC:24525GenCCUniProt (Q9Y4U1)AlphaFoldClinVar (MMACHC)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~13.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

methylmalonic aciduria and homocystinuria type cblCDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010184

Submitter: Myriad Women's Health

methylmalonic aciduria and homocystinuria type cblCSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010184

Submitter: Labcorp Genetics (formerly Invitae)

methylmalonic aciduria and homocystinuria type cblCSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010184

Submitter: PanelApp Australia

methylmalonic aciduria and homocystinuria type cblCSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010184

Submitter: Orphanet

methylmalonic aciduria and homocystinuria type cblCDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010184

Submitter: Natera

methylmalonic aciduria and homocystinuria type cblCSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010184

Submitter: Ambry Genetics

methylmalonic aciduria and homocystinuria type cblCDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010184

Submitter: G2P

methylmalonic aciduria and homocystinuria type cblCDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010184

Submitter: ClinGen

MMACHC was first reported in relation to autosomal recessive inheritance of methylmalonic aciduria and homocystinuria type cblC in 2007 (Lerner-Ellis et al. PMID: 16311595). At least 93 unique variants (including many missense, nonsense, and small deletions or insertions, as well as some splicing variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 19 probands in 7 publications (PMIDs: 26149271, 28693988, 18164228, 16963011, 30157807, 16311595, 23580368). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by experimental evidence of the biochemical function, functional alteration in non-patient cells, rescue in patient cells, and a mouse model (PMIDs: 18779575, 19700356, 24889031, 16311595) . In summary, MMACHC is definitively associated with autosomal recessive inheritance of methylmalonic aciduria and homocystinuria type cblC. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Methylmalonic aciduria and homocystinuria, cblC typeAR/Digenic

Manifestation: Biochemical; Cardiovascular; Dermatologic; Hematologic; Neurologic; Ophthalmologic; Renal

Intervention: Biochemical

Rationale: While no treatment is completely effective, specific dietary (eg, high-calorie, low protein diet and avoidance of fasting, with measures taken to avoid/treat decompensation) and other medical measures (eg, cofactor therapy) may be beneficial to treat and prevent sequelae in the acute and chronic states

Comments: Compound heterozygosity and digenic inheritance (with PRDX1) has been described

Refs: 5779140; 6749192; 3257264; 2368803; 9266389; 11258350; 10399092; 11320193; 12210350; 16311595; 16714133; 17431913; 17853453; 20301503; 19370762; 20631720; 21748409; 21835369; 23837176; 29302025; 34652574Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MMACHC variants in ClinVar

20 Conditions Cataloged
Cobalamin C diseaseTotal: 552
not providedTotal: 116
not specifiedTotal: 64
Inborn genetic diseasesTotal: 52
MMACHC-related disorderTotal: 49
Disorders of Intracellular Cobalamin MetabolismTotal: 32
See casesTotal: 4
METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENICTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015506.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
1
clinvar
2
clinvar
149
clinvar
1
clinvar
 154
missense
7
clinvar
38
clinvar
141
clinvar
16
clinvar
1
clinvar
 203
nonsense
22
clinvar
16
clinvar
2
clinvar
 40
start loss
3
clinvar
3
clinvar
 6
frameshift
37
clinvar
44
clinvar
10
clinvar
 91
splice donor/acceptor (+/-2bp)
5
clinvar
13
clinvar
1
clinvar
 19
Total751151551662513

Highest pathogenic variant AF is 0.0010327315

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_015506.3RefSeqNP_056321.24MANE Select
ENST00000401061.9EnsemblENSP00000383840.44MANE Select
NM_001330540.2RefSeqNP_001317469.13Standard
ENST00000616135.1EnsemblENSP00000478859.13Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
mmachcDanio rerio

Structure: ceratobranchial cartilage

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Vitamin digestion and absorption - Homo sapiens (human)
  • Cobalamin (Cbl, vitamin B12) transport and metabolism
  • Metabolism
  • Metabolism of water-soluble vitamins and cofactors
  • Metabolism of vitamins and cofactors

Biological Process

  • glutathione metabolic process
  • cobalamin metabolic process
  • cobalamin biosynthetic process
  • oxidation-reduction process
  • demethylation

Molecular Function

  • protein binding
  • oxidoreductase activity
  • cobalamin binding
  • demethylase activity
  • cyanocobalamin reductase (cyanide-eliminating) activity

Cellular Component

  • cytoplasm
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000401061
Coding exons
4
Length
11015
Individuals with no LoFs
124377
Homozygous LoFs
0
Heterozygous LoFs
440
Defined
124817
p
0.00176
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-1.082131731.230.00001001801
Missense (PolyPhen)6451.2841.248565
Synonymous-1.658366.01.260.00000349611
Loss of Function-0.7641814.81.210.00000108116

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000970.00097rare
Latino/Admixed American0.00300.0030notable
Ashkenazi Jewish0.00280.0028notable
East Asian0.00120.0012notable
Finnish0.0000930.000093rare
European (Non-Finnish)0.00190.0019notable
South Asian0.00130.0013notable
Other0.00210.0021notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Catalyzes the reductive dealkylation of cyanocobalamin to cob(II)alamin, using FAD or FMN as cofactor and NADPH as cosubstrate (PubMed:19700356, PubMed:21697092, PubMed:22642810). Can also catalyze the glutathione-dependent reductive demethylation of methylcobalamin, and, with much lower efficiency, the glutathione-dependent reductive demethylation of adenosylcobalamin (PubMed:19801555, PubMed:22642810, PubMed:25809485). Under anaerobic conditions cob(I)alamin is the first product; it is highly reactive and is converted to aquocob(II)alamin in the presence of oxygen (PubMed:19801555). Binds cyanocobalamin, adenosylcobalamin, methylcobalamin and other, related vitamin B12 derivatives (PubMed:21071249). {ECO:0000269|PubMed:19700356, ECO:0000269|PubMed:19801555, ECO:0000269|PubMed:21071249, ECO:0000269|PubMed:21697092, ECO:0000269|PubMed:22642810, ECO:0000269|PubMed:25809485}.;

Recessive Scores

pRec
0.166

Intolerance Scores

LoFtool
0.318
RVIS EVS
-0.13
RVIS percentile EVS
43.91

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.578

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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