3-methylcrotonyl-CoA carboxylase deficiency

Summary

3-methylcrotonyl-CoA carboxylase deficiency (MONDO:0018950) is a disease caused by variants in MCCC1 and MCCC2, with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal genes: MCCC1 (GenCC Definitive), MCCC2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 114
• Phenotypes (HPO): 10
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	2.65	Europe	Validated
Prevalence at birth	1-9 / 100 000	1.9	United States	Validated
Prevalence at birth	1-9 / 100 000	3.3	Germany	Validated
Prevalence at birth	1-9 / 100 000	1.36	Taiwan, Province of China	Validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001943	Hypoglycemia	Very frequent (80-99%)
HP:0001992	Organic aciduria	Very frequent (80-99%)
HP:0004357	Abnormality of leucine metabolism	Very frequent (80-99%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0100659	Abnormality of the cerebral vasculature	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	3-methylcrotonyl-CoA carboxylase deficiency
Mondo ID	MONDO:0018950
OMIM	210200
Orphanet	6
DOID	DOID:0050710
NCIT	C98674
SNOMED CT	13144005
UMLS	C4551505
MedGen	1633312
GARD	0010954
Is cancer (heuristic)	no

Also known as: 3-MCC deficiency · 3-methylcrotonyl-CoA carboxylase deficiency · 3-methylcrotonylglycinuria · MCC deficiency · MCCD · Methylcrotonyl-CoA carboxylase deficiency

Data availability: 114 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › classic organic aciduria › 3-methylcrotonyl-CoA carboxylase deficiency

Related subtypes (14): beta-ketothiolase deficiency, 3-hydroxyisobutyric aciduria, isovaleric acidemia, 3-hydroxy-3-methylglutaric aciduria, 3-hydroxyisobutyryl-CoA hydrolase deficiency, methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, propionic acidemia, 2-methylbutyryl-CoA dehydrogenase deficiency, isobutyryl-CoA dehydrogenase deficiency, combined malonic and methylmalonic acidemia, multiple carboxylase deficiency, methylmalonic aciduria and homocystinuria, vitamin B12-responsive methylmalonic acidemia, 3-methylglutaconic aciduria

Subtypes (2): 3-methylcrotonyl-CoA carboxylase 1 deficiency, 3-methylcrotonyl-CoA carboxylase 2 deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

114 retrieved; paginated sample, class counts are floors:

35 uncertain significance, 28 pathogenic/likely pathogenic, 13 likely benign, 12 conflicting classifications of pathogenicity, 10 likely pathogenic, 9 pathogenic, 4 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
167267	NM_020166.5(MCCC1):c.1905del (p.Lys635fs)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804815	NM_020166.5(MCCC1):c.288T>A (p.Tyr96Ter)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1929	NM_020166.5(MCCC1):c.974T>G (p.Met325Arg)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1930	NM_020166.5(MCCC1):c.1155A>C (p.Arg385Ser)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
193913	NM_020166.5(MCCC1):c.1114C>T (p.Gln372Ter)	MCCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
203795	NM_020166.5(MCCC1):c.841C>T (p.Arg281Ter)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203796	NM_020166.5(MCCC1):c.1331G>A (p.Arg444His)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265231	NM_020166.5(MCCC1):c.980C>G (p.Ser327Ter)	MCCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
344312	NM_020166.5(MCCC1):c.640_641delGG	MCCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
476391	NM_020166.5(MCCC1):c.1261C>T (p.Arg421Trp)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
476400	NM_020166.5(MCCC1):c.863A>G (p.Glu288Gly)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
649327	NM_020166.5(MCCC1):c.1303G>A (p.Ala435Thr)	MCCC1	Pathogenic	criteria provided, single submitter
654523	NM_020166.5(MCCC1):c.558del (p.Gln186fs)	MCCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
664032	NM_020166.5(MCCC1):c.1302T>G (p.Ile434Met)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1477647	NM_022132.5(MCCC2):c.1189C>G (p.Pro397Ala)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1483421	NM_022132.5(MCCC2):c.1208A>G (p.Asn403Ser)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1521043	NM_022132.5(MCCC2):c.1054G>A (p.Gly352Arg)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705095	NM_022132.5(MCCC2):c.1570G>A (p.Ala524Thr)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1920	NM_022132.5(MCCC2):c.295G>C (p.Glu99Gln)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1922	NM_022132.5(MCCC2):c.929C>G (p.Pro310Arg)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1923	NM_022132.5(MCCC2):c.499T>C (p.Cys167Arg)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1925	NM_022132.5(MCCC2):c.1309A>G (p.Ile437Val)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198252	NM_022132.5(MCCC2):c.568C>T (p.His190Tyr)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203804	NM_022132.5(MCCC2):c.577C>T (p.Arg193Cys)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203805	NM_022132.5(MCCC2):c.1015G>A (p.Val339Met)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203806	NM_022132.5(MCCC2):c.1065A>T (p.Leu355Phe)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627306	NM_022132.5(MCCC2):c.1131_1132del (p.Phe377_Ser378insTer)	MCCC2	Pathogenic	criteria provided, single submitter
4536871	NC_000005.9:g.(70900296_70922466)(70954534?)del	MCCC2	Pathogenic	criteria provided, single submitter
4536889	NC_000005.9:g.(70900296_70922466)(70954533?)del	MCCC2	Pathogenic	criteria provided, single submitter
4536929	NC_000005.9:g.(70900296_70922466)_(70946011_70948495)del	MCCC2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MCCC1	Definitive	Autosomal recessive	3-methylcrotonyl-CoA carboxylase 1 deficiency	6
MCCC2	Definitive	Autosomal recessive	3-methylcrotonyl-CoA carboxylase 2 deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MCCC1	Orphanet:6	3-methylcrotonyl-CoA carboxylase deficiency
MCCC2	Orphanet:6	3-methylcrotonyl-CoA carboxylase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MCCC1	HGNC:6936	ENSG00000078070	Q96RQ3	Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial	gencc,clinvar
MCCC2	HGNC:6937	ENSG00000131844	Q9HCC0	Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MCCC1	Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial	Biotin-attachment subunit of the 3-methylcrotonyl-CoA carboxylase, an enzyme that catalyzes the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step for leucine and isovaleric acid catabolism.
MCCC2	Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial	Carboxyltransferase subunit of the 3-methylcrotonyl-CoA carboxylase, an enzyme that catalyzes the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step for leucine and isovaleric acid catabolism.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MCCC1	Other/Unknown	no		Biotin_lipoyl, Biotin_BS, CPAse_ATP-bd
MCCC2	Other/Unknown	no		COA_CT_N, COA_CT_C, ClpP/crotonase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
metanephros cortex	1
right lobe of liver	1
left ventricle myocardium	1
right adrenal gland cortex	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MCCC1	286	ubiquitous	marker	body of pancreas, metanephros cortex, right lobe of liver
MCCC2	272	ubiquitous	marker	left ventricle myocardium, right adrenal gland cortex, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCCC2	2,500
MCCC1	2,322

Intra-cohort edges

A	B	Sources
MCCC1	MCCC2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCCC1	Q96RQ3	14
MCCC2	Q9HCC0	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
3-Methylcrotonyl-CoA carboxylase deficiency	2	5710.0×	2e-07	MCCC1, MCCC2
Defects in biotin (Btn) metabolism	2	2284.0×	1e-06	MCCC1, MCCC2
Diseases of branched-chain amino acid catabolism	2	1903.3×	1e-06	MCCC1, MCCC2
Defective HLCS causes multiple carboxylase deficiency	2	1631.4×	1e-06	MCCC1, MCCC2
Biotin transport and metabolism	2	1038.2×	2e-06	MCCC1, MCCC2
Defects in vitamin and cofactor metabolism	2	601.0×	6e-06	MCCC1, MCCC2
Branched-chain amino acid catabolism	2	475.8×	8e-06	MCCC1, MCCC2
Metabolism of water-soluble vitamins and cofactors	2	181.3×	5e-05	MCCC1, MCCC2
Metabolism of vitamins and cofactors	2	116.5×	1e-04	MCCC1, MCCC2
Diseases of metabolism	2	80.4×	2e-04	MCCC1, MCCC2
Metabolism of amino acids and derivatives	2	67.6×	3e-04	MCCC1, MCCC2
Disease	2	13.1×	0.006	MCCC1, MCCC2
Metabolism	2	11.6×	0.007	MCCC1, MCCC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-leucine catabolic process	2	2407.4×	6e-07	MCCC1, MCCC2
branched-chain amino acid catabolic process	2	1053.2×	2e-06	MCCC1, MCCC2
biotin metabolic process	1	2106.5×	6e-04	MCCC1
coenzyme A metabolic process	1	1685.2×	6e-04	MCCC2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MCCC1	0	0
MCCC2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MCCC1	2	Binding:2
MCCC2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MCCC1, MCCC2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MCCC1	2	—
MCCC2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan