MMACHC

metabolism of cobalamin associated C

Basic information

Region (hg38): 1:45500300-45513382

Links

ENSG00000132763NCBI:25974OMIM:609831HGNC:24525Uniprot:Q9Y4U1AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • methylmalonic aciduria and homocystinuria type cblC (Definitive), mode of inheritance: AR
  • methylmalonic aciduria and homocystinuria type cblC (Definitive), mode of inheritance: AR
  • methylmalonic aciduria and homocystinuria type cblC (Strong), mode of inheritance: AR
  • methylmalonic aciduria and homocystinuria type cblC (Strong), mode of inheritance: AR
  • methylmalonic aciduria and homocystinuria type cblC (Supportive), mode of inheritance: AR
  • methylmalonic aciduria and homocystinuria type cblC (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Methylmalonic aciduria and homocystinuria, cblC typeAR/DigenicBiochemicalWhile 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 statesBiochemical; Cardiovascular; Dermatologic; Hematologic; Neurologic; Ophthalmologic; Renal5779140; 6749192; 3257264; 2368803; 9266389; 11258350; 10399092; 11320193; 12210350; 16311595; 16714133; 17431913; 17853453; 20301503; 19370762; 20631720; 21748409; 21835369; 23837176; 29302025; 34652574
Compound heterozygosity and digenic inheritance (with PRDX1) has been described

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MMACHC gene.

  • Cobalamin C disease (73 variants)
  • Methylmalonic acidemia with homocystinuria cblC (21 variants)
  • not provided (19 variants)
  • Disorders of Intracellular Cobalamin Metabolism (5 variants)
  • not specified (2 variants)
  • Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (2 variants)
  • Inborn genetic diseases (2 variants)
  • METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC (2 variants)
  • MMACHC-related disorder (2 variants)
  • Abnormality of metabolism/homeostasis (1 variants)
  • See cases (1 variants)
  • cblC type of combined methylmalonic aciduria and homocystinuria (1 variants)
  • Atypical hemolytic-uremic syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MMACHC gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
138
clinvar
2
clinvar
140
missense
7
clinvar
20
clinvar
100
clinvar
6
clinvar
1
clinvar
134
nonsense
21
clinvar
11
clinvar
2
clinvar
34
start loss
3
clinvar
2
clinvar
5
frameshift
34
clinvar
25
clinvar
9
clinvar
68
inframe indel
1
clinvar
2
clinvar
9
clinvar
12
splice donor/acceptor (+/-2bp)
6
clinvar
8
clinvar
14
splice region
1
1
11
13
non coding
1
clinvar
48
clinvar
50
clinvar
21
clinvar
120
Total 73 68 168 194 24

Highest pathogenic variant AF is 0.000985

Variants in MMACHC

This is a list of pathogenic ClinVar variants found in the MMACHC region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
1-45500308-G-A Disorders of Intracellular Cobalamin Metabolism Uncertain significance (Jan 13, 2018)297478
1-45500333-A-G Cobalamin C disease • Methylmalonic acidemia with homocystinuria cblC Pathogenic (Dec 26, 2023)381577
1-45500333-A-T Cobalamin C disease Pathogenic (Sep 05, 2023)2725295
1-45500334-T-C Cobalamin C disease Pathogenic/Likely pathogenic (Oct 26, 2023)556190
1-45500334-T-G Cobalamin C disease Pathogenic/Likely pathogenic (Apr 11, 2023)557424
1-45500335-G-A Cobalamin C disease • Methylmalonic acidemia with homocystinuria cblC Pathogenic (Sep 24, 2023)203823
1-45500340-C-G Cobalamin C disease Conflicting classifications of pathogenicity (Jan 04, 2024)1545615
1-45500341-G-A Cobalamin C disease Likely benign (Jul 25, 2023)2726416
1-45500344-AGTCGCAGAGCT-A Cobalamin C disease Pathogenic (May 28, 2022)2202756
1-45500346-T-A Cobalamin C disease Uncertain significance (Aug 31, 2021)1405023
1-45500347-C-T Cobalamin C disease Likely benign (Oct 17, 2022)1550373
1-45500351-G-A Cobalamin C disease Conflicting classifications of pathogenicity (Jan 19, 2024)973438
1-45500359-G-A Cobalamin C disease Likely benign (Jan 21, 2023)2882337
1-45500362-G-A Cobalamin C disease Likely benign (Mar 14, 2023)2845371
1-45500365-G-A Cobalamin C disease Likely benign (Oct 26, 2023)799351
1-45500365-G-T Inborn genetic diseases Uncertain significance (May 17, 2023)2546878
1-45500367-TC-T Cobalamin C disease Pathogenic (Dec 29, 2022)2824664
1-45500368-C-T Cobalamin C disease Likely benign (Dec 10, 2022)2820052
1-45500370-A-C Cobalamin C disease Uncertain significance (Nov 14, 2021)1358074
1-45500372-G-A Cobalamin C disease • MMACHC-related disorder Likely benign (Jan 17, 2024)582169
1-45500374-C-T Cobalamin C disease Likely benign (Nov 27, 2023)1104374
1-45500377-G-A Cobalamin C disease Likely benign (May 27, 2023)1623770
1-45500377-G-C Cobalamin C disease Likely benign (Feb 07, 2023)1982366
1-45500378-C-T Cobalamin C disease Likely benign (Jun 02, 2023)2782219
1-45500378-CTA-C Cobalamin C disease Pathogenic (Apr 26, 2020)1076553

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
MMACHCprotein_codingprotein_codingENST00000401061 411015
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
1.14e-130.0062012437704401248170.00176
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense-1.082131731.230.00001001801
Missense in Polyphen6451.2841.248565
Synonymous-1.658366.01.260.00000349611
Loss of Function-0.7641814.81.210.00000108116

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.003920.00392
Ashkenazi Jewish0.002780.00278
East Asian0.001170.00117
Finnish0.00009280.0000928
European (Non-Finnish)0.001930.00193
Middle Eastern0.001170.00117
South Asian0.001310.00131
Other0.002150.00214

dbNSFP

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}.;
Pathway
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 (Consensus)

Recessive Scores

pRec
0.166

Intolerance Scores

loftool
0.318
rvis_EVS
-0.13
rvis_percentile_EVS
43.91

Haploinsufficiency Scores

pHI
0.0929
hipred
N
hipred_score
0.167
ghis
0.511

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
E
gene_indispensability_score
0.578

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Mmachc
Phenotype
respiratory system phenotype; embryo phenotype; hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; vision/eye phenotype; digestive/alimentary phenotype; renal/urinary system phenotype; homeostasis/metabolism phenotype; immune system phenotype; cellular phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); craniofacial phenotype;

Zebrafish Information Network

Gene name
mmachc
Affected structure
ceratobranchial cartilage
Phenotype tag
abnormal
Phenotype quality
absent

Gene ontology

Biological process
glutathione metabolic process;cobalamin metabolic process;cobalamin biosynthetic process;oxidation-reduction process;demethylation
Cellular component
cytoplasm;cytosol
Molecular function
protein binding;oxidoreductase activity;cobalamin binding;demethylase activity;cyanocobalamin reductase (cyanide-eliminating) activity;protein homodimerization activity;glutathione binding;FAD binding