MCCC1

protein-coding

methylcrotonyl-CoA carboxylase subunit 1, the group of Methylcrotonyl-CoA carboxylase subunits

Gene summary

This gene encodes the large subunit of 3-methylcrotonyl-CoA carboxylase. This enzyme functions as a heterodimer and catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA. Mutations in this gene are associated with 3-Methylcrotonylglycinuria, an autosomal recessive disorder of leucine catabolism. [provided by RefSeq, Jul 2008]

MANE transcript

NM_020166.5

Inheritance

ClinVar variants

P:222U:306B:231

Top phenotype

3-Methylcrotonyl-CoA carboxylase 1 deficiency

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr3:183,015,218-183,116,075

External References & Databases

Ensembl (ENSG00000078070)

Transcript & Mutation Effects

hg38 • Region Span ~100.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

3-methylcrotonyl-CoA carboxylase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018950

Submitter: ClinGen

The relationship between MCCC1 and 3-methylcrotonyl-CoA carboxylase deficiency (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of August, 2019. MCCC1 encodes the alpha subunit of 3-methylcrotonyl-CoA carboxylase, which is involved in the catabolism of leucine. Deficiency of MCCC1 is associated with increased urinary excretion of 3-hydroxyisovalerate & 3-methylcrotonylglycine, The clinical phenotype ranges from severe neurological abnormalities and death in infancy to asymptomatic. Variants in MCCC1 were ﬁrst reported in humans with this deﬁciency in 2001 (Gallardo et al., PMID: 11170888; Baumgartner et al., PMID: 11181649). At least 103 unique variants (missense, nonsense, frameshift, splicing, deletion) have been identiﬁed in humans (Cozzolino et al., 2018; PMID 29767664). Evidence supporting this gene-disease relationship includes case-level and experimental data. This gene-disease relationship is supported by biochemical assays, expression studies, and in vitro studies. In summary, MCCC1 is deﬁnitively associated with autosomal recessive 3-methylcrotonyl-CoA carboxylase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

3-methylcrotonyl-CoA carboxylase 1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008861

Submitter: Ambry Genetics

3-methylcrotonyl-CoA carboxylase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008861

Submitter: PanelApp Australia

3-methylcrotonyl-CoA carboxylase 1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008861

Submitter: G2P

3-methylcrotonyl-CoA carboxylase 1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008861

Submitter: Natera

3-methylcrotonyl-CoA carboxylase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008861

Submitter: Labcorp Genetics (formerly Invitae)

3-methylcrotonyl-CoA carboxylase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018950

Submitter: Orphanet

Clinical Genomic Database (CGD)

3-Methylcrotonyl-CoA carboxylase 1 deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: Therapy may not be necessary/effective in some individuals, but medical (eg, carnitine, glycine) and dietary (eg, low protein, leucine restricted) therapy may be beneficial in some individuals; Precautions in the setting of stressors such as viral illnesses may be beneficial

Refs: 4194964; 5035417; 1000869; 6441868; 2515383; 1779635; 1517917; 8598648; 9187484; 10485305; 11181649; 11170888; 11893004; 16835865; 17968484; 21734494; 22264772; 22642865; 25356967

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MCCC1 variants in ClinVar

6 Conditions Cataloged

3-methylcrotonyl-CoA carboxylase 1 deficiencyTotal: 832

not providedTotal: 127

Inborn genetic diseasesTotal: 94

MCCC1-related disorderTotal: 64

not specifiedTotal: 53

Methylcrotonyl-CoA carboxylase deficiencyTotal: 47

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020166.5. 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			14 clinvar	208 clinvar	1 clinvar	223
missense	3 clinvar	39 clinvar	285 clinvar	20 clinvar	2 clinvar	349
nonsense	23 clinvar	22 clinvar	4 clinvar			49
start loss	1 clinvar	1 clinvar				2
frameshift	40 clinvar	48 clinvar	1 clinvar			89
splice donor/acceptor (+/-2bp)	7 clinvar	38 clinvar	2 clinvar			47
Total	74	148	306	228	3	759

Highest pathogenic variant AF is 0.00015451774

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 70 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020166.5	RefSeq	NP_064551.3	19	MANE Select
ENST00000265594.9	Ensembl	ENSP00000265594.4	19	MANE Select
NM_001293273.2	RefSeq	NP_001280202.1	16	Standard
NM_001363880.1	RefSeq	NP_001350809.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Valine, leucine and isoleucine degradation - Homo sapiens (human)
3-Methylglutaconic Aciduria Type I
Valine, Leucine and Isoleucine Degradation
2-Methyl-3-Hydroxybutryl CoA Dehydrogenase Deficiency
Isovaleric Aciduria

Biological Process

leucine catabolic process
biotin metabolic process
protein heterooligomerization

Molecular Function

biotin carboxylase activity
methylcrotonoyl-CoA carboxylase activity
protein binding
ATP binding
biotin binding

Cellular Component

3-methylcrotonyl-CoA carboxylase complex, mitochondrial
mitochondrion
mitochondrial matrix
cytosol
methylcrotonoyl-CoA carboxylase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265594
Coding exons: 19
Length: 100858
Individuals with no LoFs: 125659
Homozygous LoFs: 0
Heterozygous LoFs: 89
Defined: 125748
p: 0.000354

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.543	371	402	0.924	0.0000210	4764
Missense (PolyPhen)		109	154.72	0.70448		1843
Synonymous	-0.459	151	144	1.05	0.00000844	1375
Loss of Function	2.03	24	37.4	0.641	0.00000175	464

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00055	0.00049	rare
Latino/Admixed American	0.00047	0.00046	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00038	0.00037	rare
South Asian	0.00050	0.00049	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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. {ECO:0000269|PubMed:17360195}.;
Disease: DISEASE: 3-methylcrotonoyl-CoA carboxylase 1 deficiency (MCC1D) [MIM:210200]: An autosomal recessive disorder of leucine catabolism. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3- hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency. {ECO:0000269|PubMed:11170888, ECO:0000269|PubMed:11181649, ECO:0000269|PubMed:11406611, ECO:0000269|PubMed:16010683, ECO:0000269|PubMed:17968484, ECO:0000269|PubMed:21071250, ECO:0000269|PubMed:22150417, ECO:0000269|PubMed:22264772, ECO:0000269|PubMed:22642865, ECO:0000269|PubMed:25382614, ECO:0000269|PubMed:27601257, ECO:0000269|Ref.6}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.276

Intolerance Scores

LoFtool: 0.144
RVIS EVS: -0.86
RVIS percentile EVS: 10.85

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.961

Gene Damage Prediction

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