MCCC2

protein-coding

methylcrotonyl-CoA carboxylase subunit 2, the group of Methylcrotonyl-CoA carboxylase subunits

Gene summary

This gene encodes the small 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. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2018]

MANE transcript

NM_022132.5

Inheritance

ClinVar variants

P:226U:250B:169

Top phenotype

3-Methylcrotonyl-CoA carboxylase 2 deficiency

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr5:71,579,531-71,658,706

External References & Databases

Ensembl (ENSG00000131844)

Transcript & Mutation Effects

hg38 • Region Span ~79.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

3-methylcrotonyl-CoA carboxylase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018950

Submitter: Orphanet

3-methylcrotonyl-CoA carboxylase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018950

Submitter: ClinGen

The relationship between MCCC2 and 3-methylcrotonyl-CoA carboxylase deficiency (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of September, 2019. MCCC2 encodes the beta subunit of 3-methylcrotonyl-CoA carboxylase, which is involved in the catabolism of leucine. Deficiency of MCCC2 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 MCCC2 were ﬁrst reported in humans with this deﬁciency in 2001 (Gallardo et al., PMID: 11170888; Baumgartner et al., PMID: 11181649). At least 113 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, MCCC2 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 2 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008862

Submitter: PanelApp Australia

3-methylcrotonyl-CoA carboxylase 2 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008862

Submitter: Natera

3-methylcrotonyl-CoA carboxylase 2 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008862

Submitter: G2P

3-methylcrotonyl-CoA carboxylase 2 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008862

Submitter: Labcorp Genetics (formerly Invitae)

3-methylcrotonyl-CoA carboxylase 2 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008862

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

3-Methylcrotonyl-CoA carboxylase 2 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: 7128647; 1293382; 8598650; 8831079; 9544913; 11181649; 11170888; 15877210; 16835865; 17968484; 22030835; 22264772; 22642865; 25356967

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MCCC2 variants in ClinVar

10 Conditions Cataloged

3-methylcrotonyl-CoA carboxylase 2 deficiencyTotal: 712

not providedTotal: 123

not specifiedTotal: 65

Methylcrotonyl-CoA carboxylase deficiencyTotal: 64

MCCC2-related disorderTotal: 51

Inborn genetic diseasesTotal: 51

Likely inborn error of metabolismTotal: 2

Spinal muscular atrophy, type IVTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022132.5. 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			16 clinvar	159 clinvar	2 clinvar	177
missense	5 clinvar	68 clinvar	227 clinvar	8 clinvar		308
nonsense	15 clinvar	30 clinvar	1 clinvar			46
start loss	1 clinvar					1
frameshift	33 clinvar	29 clinvar	1 clinvar			63
splice donor/acceptor (+/-2bp)	4 clinvar	41 clinvar	5 clinvar			50
Total	58	168	250	167	2	645

Highest pathogenic variant AF is 0.0006703949

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 68 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022132.5	RefSeq	NP_071415.1	17	MANE Select
ENST00000340941.11	Ensembl	ENSP00000343657.6	17	MANE Select
NM_001363147.1	RefSeq	NP_001350076.1	16	Standard
ENST00000509358.7	Ensembl	ENSP00000420994.3	12	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
coenzyme A metabolic process
protein heterooligomerization

Molecular Function

methylcrotonoyl-CoA carboxylase activity
protein binding
ATP 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: ENST00000340941
Coding exons: 17
Length: 71417
Individuals with no LoFs: 125674
Homozygous LoFs: 0
Heterozygous LoFs: 74
Defined: 125748
p: 0.000294

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.306	298	313	0.951	0.0000164	3640
Missense (PolyPhen)		122	137.71	0.88591		1633
Synonymous	0.0302	112	112	0.996	0.00000607	1097
Loss of Function	2.04	22	35.0	0.628	0.00000199	409

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00060	0.00054	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00024	0.00024	rare
South Asian	0.00049	0.00049	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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. {ECO:0000269|PubMed:17360195}.;
Disease: DISEASE: 3-methylcrotonoyl-CoA carboxylase 2 deficiency (MCC2D) [MIM:210210]: 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}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.180

Intolerance Scores

LoFtool: 0.206
RVIS EVS: -0.22
RVIS percentile EVS: 37.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.977

Gene Damage Prediction

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