MMADHC

metabolism of cobalamin associated D

Basic information

Region (hg38): 2:149569636-149587778

Previous symbols: [ "C2orf25" ]

Links

ENSG00000168288 ∙ NCBI:27249 ∙ OMIM:611935 ∙ HGNC:25221 ∙ Uniprot:Q9H3L0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• methylmalonic aciduria and homocystinuria type cblD (Definitive), mode of inheritance: AR
• methylmalonic aciduria and homocystinuria type cblD (Moderate), mode of inheritance: AR
• methylmalonic aciduria and homocystinuria type cblD (Strong), mode of inheritance: AR
• methylmalonic aciduria and homocystinuria type cblD (Supportive), mode of inheritance: AR
• inborn disorder of cobalamin metabolism and transport (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Methylmalonic aciduria and homocystinuria, cblD type	AR	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; Hematologic; Neurologic; Ophthalmologic	5524089; 2339678; 15292234; 18385497; 20301409; 20301503; 22156578

ClinVar

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

• Methylmalonic aciduria and homocystinuria type cblD (26 variants)
• not provided (2 variants)
• Vitamin B12-responsive methylmalonic acidemia, type cblDv2 (2 variants)
• Cobalamin C disease (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MMADHC 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				92	2	94
missense		1	47	4	2	54
nonsense	11	7	2			20
start loss						0
frameshift	16	9	1			26
inframe indel			1			1
splice donor/acceptor (+/-2bp)		14				14
splice region			7	28	1	36
non coding			4	62	20	86
Total	27	31	55	158	24

Highest pathogenic variant AF is 0.0000197

Variants in MMADHC

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

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

Position	Type	Phenotype	Significance	ClinVar
2-149569707-A-G		Disorders of Intracellular Cobalamin Metabolism • Methylmalonic aciduria and homocystinuria type cblD	Uncertain significance (Jan 13, 2018)
2-149569733-T-C		Methylmalonic aciduria and homocystinuria type cblD • Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Jan 13, 2018)
2-149569810-T-C		Methylmalonic aciduria and homocystinuria type cblD • Disorders of Intracellular Cobalamin Metabolism	Benign (Jan 12, 2018)
2-149569848-T-C		Methylmalonic aciduria and homocystinuria type cblD • Disorders of Intracellular Cobalamin Metabolism	Benign (Jun 29, 2018)
2-149569885-A-G		Methylmalonic aciduria and homocystinuria type cblD • Disorders of Intracellular Cobalamin Metabolism	Benign (Jun 29, 2018)
2-149569974-C-T		Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Oct 19, 2023)
2-149569980-T-C		Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Jan 28, 2023)
2-149569980-T-G		Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Jul 02, 2021)
2-149569988-A-G		Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Jul 03, 2022)
2-149569989-T-C		Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Nov 22, 2021)
2-149569996-A-C		Methylmalonic aciduria and homocystinuria type cblD	Uncertain significance (Sep 04, 2020)
2-149570001-A-G		Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Nov 05, 2023)
2-149570008-T-G		Methylmalonic aciduria and homocystinuria type cblD	Uncertain significance (Aug 17, 2022)
2-149570010-T-A		Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Jan 28, 2024)
2-149570019-A-G		Methylmalonic aciduria and homocystinuria type cblD	Benign (Feb 01, 2024)
2-149570020-T-C		Inborn genetic diseases	Uncertain significance (Nov 27, 2023)
2-149570025-G-A		Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Mar 25, 2021)
2-149570030-T-C		Methylmalonic aciduria and homocystinuria type cblD	Uncertain significance (Mar 29, 2022)
2-149570037-T-C		Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Dec 14, 2023)
2-149570040-A-G		Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Feb 25, 2023)
2-149570043-T-C		Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Jul 09, 2020)
2-149570046-A-G		not specified • Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Nov 08, 2023)
2-149570057-A-G		Methylmalonic aciduria and homocystinuria type cblD	Uncertain significance (Aug 24, 2021)
2-149570065-T-C		Disorders of Intracellular Cobalamin Metabolism • Methylmalonic aciduria and homocystinuria type cblD	Uncertain significance (Jan 13, 2018)
2-149570070-A-G		Methylmalonic aciduria and homocystinuria type cblD	Likely benign (Aug 22, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MMADHC	protein_coding	protein_coding	ENST00000428879	7	18183

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000207	0.908	125716	0	24	125740	0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.413	168	154	1.09	0.00000713	1934
Missense in Polyphen		50	49.785	1.0043		600
Synonymous	-0.246	54	51.7	1.04	0.00000237	565
Loss of Function	1.58	10	17.1	0.586	0.00000102	187

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000119	0.000119
Ashkenazi Jewish	0.00	0.00
East Asian	0.000273	0.000272
Finnish	0.00	0.00
European (Non-Finnish)	0.000123	0.000123
Middle Eastern	0.000273	0.000272
South Asian	0.0000328	0.0000327
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in cobalamin metabolism (PubMed:18385497, PubMed:23415655, PubMed:24722857, PubMed:26364851). Plays a role in regulating the biosynthesis of two coenzymes, methylcobalamin and adenosylcobalamin (PubMed:18385497, PubMed:24722857). Plays a role in regulating the proportion of methylcobalamin and adenosylcobalamin (PubMed:23415655, PubMed:24722857). Promotes oxidation of cob(II)alamin bound to MMACHC (PubMed:26364851). {ECO:0000269|PubMed:18385497, ECO:0000269|PubMed:23415655, ECO:0000269|PubMed:24722857, ECO:0000269|PubMed:26364851}.
• Pathway: Cobalamin (Cbl, vitamin B12) transport and metabolism;Metabolism;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors (Consensus)

Recessive Scores

• pRec: 0.133

Intolerance Scores

• loftool: 0.313
• rvis_EVS: 0.48
• rvis_percentile_EVS: 79.25

Haploinsufficiency Scores

• pHI: 0.174
• hipred: N
• hipred_score: 0.333
• ghis: 0.472

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.531

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mmadhc

Gene ontology

• Biological process: coenzyme biosynthetic process;cobalamin metabolic process
• Cellular component: cytoplasm;mitochondrion;cytosol
• Molecular function: protein binding