MMACHC

metabolism of cobalamin associated C

Basic information

Region (hg38): 1:45500299-45513382

Links

ENSG00000132763 ∙ NCBI:25974 ∙ OMIM:609831 ∙ HGNC:24525 ∙ Uniprot:Q9Y4U1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

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

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Methylmalonic aciduria and homocystinuria, cblC type	AR/Digenic	Biochemical	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	Biochemical; Cardiovascular; Dermatologic; Hematologic; Neurologic; Ophthalmologic; Renal	5779140; 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 (419 variants)
• Disorders of Intracellular Cobalamin Metabolism (96 variants)
• not provided (93 variants)
• Methylmalonic acidemia with homocystinuria cblC (50 variants)
• Inborn genetic diseases (26 variants)
• not specified (25 variants)
• See cases (4 variants)
• MMACHC-related condition (4 variants)
• METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC (3 variants)
• Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (2 variants)
• Abnormality of metabolism/homeostasis (1 variants)
• cblC type of combined methylmalonic aciduria and homocystinuria (1 variants)
• Atypical hemolytic-uremic syndrome (1 variants)
• Methylmalonic aciduria, type cblc (1 variants)
• Methylmalonic aciduria;Homocystinuria (1 variants)
• Retinal dystrophy (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				117	2	119
missense	7	19	98	4	1	129
nonsense	21	10	1			32
start loss	3	2				5
frameshift	27	25	8			60
inframe indel	1	1	10			12
splice donor/acceptor (+/-2bp)	5	6				11
splice region		1	1	9		11
non coding	1		48	32	20	101
Total	65	63	165	153	23

Highest pathogenic variant AF is 0.000105

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)
1-45500333-A-G		Methylmalonic acidemia with homocystinuria cblC • Cobalamin C disease	Pathogenic (Dec 26, 2023)
1-45500333-A-T		Cobalamin C disease	Pathogenic (Sep 05, 2023)
1-45500334-T-C		Cobalamin C disease	Pathogenic/Likely pathogenic (Oct 26, 2023)
1-45500334-T-G		Cobalamin C disease	Pathogenic/Likely pathogenic (Apr 11, 2023)
1-45500335-G-A		Cobalamin C disease • Methylmalonic acidemia with homocystinuria cblC	Pathogenic (Sep 24, 2023)
1-45500340-C-G		Cobalamin C disease	Conflicting classifications of pathogenicity (Jan 04, 2024)
1-45500341-G-A		Cobalamin C disease	Likely benign (Jul 25, 2023)
1-45500344-AGTCGCAGAGCT-A		Cobalamin C disease	Pathogenic (May 28, 2022)
1-45500346-T-A		Cobalamin C disease	Uncertain significance (Aug 31, 2021)
1-45500347-C-T		Cobalamin C disease	Likely benign (Oct 17, 2022)
1-45500351-G-A		Cobalamin C disease	Conflicting classifications of pathogenicity (Jan 19, 2024)
1-45500359-G-A		Cobalamin C disease	Likely benign (Jan 21, 2023)
1-45500362-G-A		Cobalamin C disease	Likely benign (Mar 14, 2023)
1-45500365-G-A		Cobalamin C disease	Likely benign (Oct 26, 2023)
1-45500365-G-T		Inborn genetic diseases	Uncertain significance (May 17, 2023)
1-45500367-TC-T		Cobalamin C disease	Pathogenic (Dec 29, 2022)
1-45500368-C-T		Cobalamin C disease	Likely benign (Dec 10, 2022)
1-45500370-A-C		Cobalamin C disease	Uncertain significance (Nov 14, 2021)
1-45500372-G-A		Cobalamin C disease • MMACHC-related disorder	Likely benign (Jan 17, 2024)
1-45500374-C-T		Cobalamin C disease	Likely benign (Nov 27, 2023)
1-45500377-G-A		Cobalamin C disease	Likely benign (May 27, 2023)
1-45500377-G-C		Cobalamin C disease	Likely benign (Feb 07, 2023)
1-45500378-C-T		Cobalamin C disease	Likely benign (Jun 02, 2023)
1-45500378-CTA-C		Cobalamin C disease	Pathogenic (Apr 26, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MMACHC	protein_coding	protein_coding	ENST00000401061	4	11015

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.14e-13	0.00620	124377	0	440	124817	0.00176

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.08	213	173	1.23	0.0000100	1801
Missense in Polyphen		64	51.284	1.248		565
Synonymous	-1.65	83	66.0	1.26	0.00000349	611
Loss of Function	-0.764	18	14.8	1.21	0.00000108	116

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00392	0.00392
Ashkenazi Jewish	0.00278	0.00278
East Asian	0.00117	0.00117
Finnish	0.0000928	0.0000928
European (Non-Finnish)	0.00193	0.00193
Middle Eastern	0.00117	0.00117
South Asian	0.00131	0.00131
Other	0.00215	0.00214

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

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

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