MMUT

protein-coding

methylmalonyl-CoA mutase

Gene summary

This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_000255.4

Inheritance

ClinVar variants

P:446U:287B:253

Top phenotype

Methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency

gnomAD constraint

pLI —, LoF o/e 0.93

Max pathogenic AF

—

Genomic locus

chr6:49,430,360-49,463,253

External References & Databases

Ensembl (ENSG00000146085)

Transcript & Mutation Effects

hg38 • Region Span ~32.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

methylmalonic aciduria due to methylmalonyl-CoA mutase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009612

Submitter: G2P

methylmalonic aciduria due to methylmalonyl-CoA mutase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009612

Submitter: Natera

vitamin B12-unresponsive methylmalonic acidemia type mut-SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019267

Submitter: Orphanet

vitamin B12-unresponsive methylmalonic acidemia type mut0SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017360

Submitter: Orphanet

methylmalonic aciduria due to methylmalonyl-CoA mutase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009612

Submitter: ClinGen

The relationship between MUT and methylmalonic academi¬a due to methylmalonyl-CoA deficiency, an autosomal recessive disorder of propionyl-CoA metabolism, was evaluated using the ClinGen Clinical Validity Framework as of April 25th, 2019. Methlmalonyl-CoA mutase (MCM) is a mitochondrial enzyme that catalyzes the isomerization of L-methylmalonyl-CoA to succinyl-CoA using cobalamin as a cofactor. This is a key reaction in propionyl-CoA metabolism. Variants in MCM cause the mut type of methylmalonic aciduria, including mut0 (complete deficiency) and mut- (partical deficiency). Variants in MUT causing MMA were first reported by Ledley et al in 1990 (PMID 1970180). Since then, over 250 MUT variants have been reported. Data from 14 patients with 18 unique variants (missense, nonsense, frameshift, and splicing) from 5 publications were curated (Ledley et al, 1990, PMID 1970180; Acquaviva et al, 2005, PMID 15643616; Han et al, 2015, PMID 26454439; Chu et al, 2016, PMID 27233228; Keyfi et al, 2016, PMID 26449400). This gene-disease relationship is supported by the biochemical function of methylmalonyl-CoA mutase (Goodey et al, 1972, PMID 4654847), which is consistent with the elevated MMA and propionyl carnitine observed in patients with this condition; functional studies (Forney et al, 2014; PMID 25125334); mouse models (including Forney et al, PMID 27519416) and the results of gene therapy in a knockout mouse (Carrillo-Carrasco et al, 2010, PMID 20486773). This curation and includes data provided by Counsyl. In summary, MUT is definitively associated with autosomal recessive methylmalonic aciduria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation included data collected by Counsyl. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on May 9th, 2019.

methylmalonic aciduria due to methylmalonyl-CoA mutase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009612

Submitter: Labcorp Genetics (formerly Invitae)

methylmalonic aciduria due to methylmalonyl-CoA mutase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009612

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Methylmalonic acidemia due to methylmalonyl-CoA mutase deficiencyAR

Manifestation: Biochemical; Hematologic; Cardiovascular; 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

Refs: 6132336; 1977311; 1970180; 1968706; 1346616; 1351030; 7681251; 15643616; 12948746; 16451139; 18563634; 20301409; 22614770; 22695176

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MMUT variants in ClinVar

17 Conditions Cataloged

not providedTotal: 875

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiencyTotal: 409

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiencyTotal: 223

not specifiedTotal: 160

Methylmalonic acidemiaTotal: 83

MMUT-related disorderTotal: 39

METHYLMALONIC ACIDURIA, mut(0) TYPETotal: 14

MUT-related disordersTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000255.4. 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			8 clinvar	237 clinvar	3 clinvar	248
missense	60 clinvar	135 clinvar	272 clinvar	12 clinvar	1 clinvar	480
nonsense	56 clinvar	28 clinvar				84
start loss	2 clinvar					2
frameshift	83 clinvar	39 clinvar	3 clinvar			125
splice donor/acceptor (+/-2bp)	17 clinvar	26 clinvar	4 clinvar			47
Total	218	228	287	249	4	986

Highest pathogenic variant AF is 0.000208783

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000255.4	RefSeq	NP_000246.2	12	MANE Select
ENST00000274813.4	Ensembl	ENSP00000274813.3	12	MANE Select
ENST00000878060.1	Ensembl	ENSP00000548119.1	12	Standard
ENST00000878060.2	Ensembl	ENSP00000548119.1	12	Standard

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000274813
Coding exons: 12
Length: 32832
Individuals with no LoFs: 125570
Homozygous LoFs: 0
Heterozygous LoFs: 178
Defined: 125748
p: 0.000708

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.229	401	414	0.968	0.0000212	4896
Missense (PolyPhen)		169	194.83	0.8674		2234
Synonymous	0.0118	132	132	0.999	0.00000628	1484
Loss of Function	0.402	35	37.7	0.929	0.00000228	415

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.00087	0.00087	rare
Ashkenazi Jewish	0.0015	0.0015	notable
East Asian	0.0014	0.0014	notable
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00048	0.00044	rare
South Asian	0.0011	0.0011	notable
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the degradation of several amino acids, odd- chain fatty acids and cholesterol via propionyl-CoA to the tricarboxylic acid cycle. MCM has different functions in other species.;
Disease: DISEASE: Methylmalonic aciduria type mut (MMAM) [MIM:251000]: An often fatal disorder of organic acid metabolism. Common clinical features include lethargy, vomiting, failure to thrive, hypotonia, neurological deficit and early death. Two forms of the disease are distinguished by the presence (mut-) or absence (mut0) of residual enzyme activity. Mut0 patients have more severe neurological manifestations of the disease than do MUT- patients. MMAM is unresponsive to vitamin B12 therapy. {ECO:0000269|PubMed:10923046, ECO:0000269|PubMed:11350191, ECO:0000269|PubMed:1346616, ECO:0000269|PubMed:1351030, ECO:0000269|PubMed:15643616, ECO:0000269|PubMed:15781192, ECO:0000269|PubMed:16281286, ECO:0000269|PubMed:1670635, ECO:0000269|PubMed:17113806, ECO:0000269|PubMed:17957493, ECO:0000269|PubMed:19588269, ECO:0000269|PubMed:1977311, ECO:0000269|PubMed:1980486, ECO:0000269|PubMed:22727635, ECO:0000269|PubMed:25125334, ECO:0000269|PubMed:26615597, ECO:0000269|PubMed:27167370, ECO:0000269|PubMed:28101778, ECO:0000269|PubMed:7909321, ECO:0000269|PubMed:7912889, ECO:0000269|PubMed:9285782, ECO:0000269|PubMed:9452100, ECO:0000269|PubMed:9554742}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.691

Intolerance Scores

RVIS EVS: 0.2
RVIS percentile EVS: 67.36

Essentials

Essential (gene trap): N