MCCC1

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

Basic information

Region (hg38): 3:183015218-183116075

Links

ENSG00000078070 ∙ NCBI:56922 ∙ OMIM:609010 ∙ HGNC:6936 ∙ Uniprot:Q96RQ3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 3-methylcrotonyl-CoA carboxylase 1 deficiency (Definitive), mode of inheritance: AR
• 3-methylcrotonyl-CoA carboxylase 1 deficiency (Strong), mode of inheritance: AR
• 3-methylcrotonyl-CoA carboxylase 1 deficiency (Definitive), mode of inheritance: AR
• 3-methylcrotonyl-CoA carboxylase deficiency (Supportive), mode of inheritance: AR
• 3-methylcrotonyl-CoA carboxylase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
3-Methylcrotonyl-CoA carboxylase 1 deficiency	AR	Biochemical	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	Biochemical; Neurologic	4194964; 5035417; 1000869; 6441868; 2515383; 1779635; 1517917; 8598648; 9187484; 10485305; 11181649; 11170888; 11893004; 16835865; 17968484; 21734494; 22264772; 22642865; 25356967

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MCCC1 gene.

• 3-methylcrotonyl-CoA carboxylase 1 deficiency (63 variants)
• not provided (14 variants)
• Methylcrotonyl-CoA carboxylase deficiency (5 variants)
• MCCC1-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MCCC1 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			1	174	1	176
missense	1	16	204	9	3	233
nonsense	25	15				40
start loss		2	1			3
frameshift	35	36	1			72
inframe indel		1	2			3
splice donor/acceptor (+/-2bp)	6	27	1			34
splice region		3	12	37	1	53
non coding			11	108	48	167
Total	67	97	221	291	52

Highest pathogenic variant AF is 0.0000722

Variants in MCCC1

This is a list of pathogenic ClinVar variants found in the MCCC1 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-183015348-C-T		3-methylcrotonyl-CoA carboxylase 1 deficiency	Uncertain significance (Jan 13, 2018)
3-183015393-T-A		3-methylcrotonyl-CoA carboxylase 1 deficiency	Uncertain significance (Jan 13, 2018)
3-183015397-GAGAGAAGACACTACTTAACTGGCCAT-G		not specified	Likely benign (Mar 17, 2016)
3-183015432-T-G		3-methylcrotonyl-CoA carboxylase 1 deficiency	Uncertain significance (Jan 12, 2018)
3-183015437-T-A		3-methylcrotonyl-CoA carboxylase 1 deficiency	Conflicting classifications of pathogenicity (Jan 23, 2018)
3-183015444-C-G		3-methylcrotonyl-CoA carboxylase 1 deficiency	Likely benign (Jul 09, 2021)
3-183015444-C-T		3-methylcrotonyl-CoA carboxylase 1 deficiency • MCCC1-related disorder	Likely benign (Nov 07, 2023)
3-183015445-G-A		3-methylcrotonyl-CoA carboxylase 1 deficiency	Conflicting classifications of pathogenicity (Jan 25, 2024)
3-183015453-T-C		3-methylcrotonyl-CoA carboxylase 1 deficiency	Likely benign (Nov 09, 2022)
3-183015456-G-A		3-methylcrotonyl-CoA carboxylase 1 deficiency	Likely benign (May 02, 2023)
3-183015467-C-T		not specified • 3-methylcrotonyl-CoA carboxylase 1 deficiency • Methylcrotonyl-CoA carboxylase deficiency	Benign (Jan 29, 2024)
3-183015480-G-A		3-methylcrotonyl-CoA carboxylase 1 deficiency	Likely benign (Dec 18, 2019)
3-183015492-G-GT		3-methylcrotonyl-CoA carboxylase 1 deficiency	Conflicting classifications of pathogenicity (Jan 16, 2024)
3-183015500-TG-T		3-methylcrotonyl-CoA carboxylase 1 deficiency	Uncertain significance (Dec 10, 2020)
3-183015522-G-A		3-methylcrotonyl-CoA carboxylase 1 deficiency	Likely benign (Nov 03, 2022)
3-183015525-C-T		3-methylcrotonyl-CoA carboxylase 1 deficiency	Likely benign (Sep 28, 2022)
3-183015526-A-G		Inborn genetic diseases	Uncertain significance (May 16, 2022)
3-183015527-C-T		Methylcrotonyl-CoA carboxylase deficiency • 3-methylcrotonyl-CoA carboxylase 1 deficiency	Uncertain significance (Jun 27, 2022)
3-183015527-C-CT		3-methylcrotonyl-CoA carboxylase 1 deficiency	Pathogenic/Likely pathogenic (Jan 29, 2024)
3-183015530-TC-T			Pathogenic (Oct 30, 2013)
3-183015531-C-T		3-methylcrotonyl-CoA carboxylase 1 deficiency • not specified	Likely benign (Aug 31, 2024)
3-183015534-T-C		3-methylcrotonyl-CoA carboxylase 1 deficiency	Likely benign (Mar 08, 2023)
3-183015536-CT-C		3-methylcrotonyl-CoA carboxylase 1 deficiency • Methylcrotonyl-CoA carboxylase deficiency • MCCC1-related disorder	Pathogenic/Likely pathogenic (Feb 16, 2024)
3-183015537-T-A		3-methylcrotonyl-CoA carboxylase 1 deficiency	Likely benign (Oct 25, 2021)
3-183015560-T-C		3-methylcrotonyl-CoA carboxylase 1 deficiency	Uncertain significance (Aug 27, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MCCC1	protein_coding	protein_coding	ENST00000265594	19	100858

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.02e-12	0.920	125659	0	89	125748	0.000354

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.543	371	402	0.924	0.0000210	4764
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00103	0.000966
Ashkenazi Jewish	0.00	0.00
East Asian	0.000326	0.000326
Finnish	0.00	0.00
European (Non-Finnish)	0.000380	0.000369
Middle Eastern	0.000326	0.000326
South Asian	0.000500	0.000490
Other	0.000326	0.000326

dbNSFP

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.
• Pathway: 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;3-Methylcrotonyl Coa Carboxylase Deficiency Type I;Propionic Acidemia;Maple Syrup Urine Disease;3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency;Isobutyryl-coa dehydrogenase deficiency;3-hydroxyisobutyric aciduria;3-hydroxyisobutyric acid dehydrogenase deficiency;Isovaleric acidemia;Methylmalonate Semialdehyde Dehydrogenase Deficiency;Methylmalonic Aciduria;3-Methylglutaconic Aciduria Type IV;3-Methylglutaconic Aciduria Type III;Beta-Ketothiolase Deficiency;Amino Acid metabolism;Biotin transport and metabolism;Branched-chain amino acid catabolism;Metabolism of amino acids and derivatives;leucine degradation;Metabolism;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors;Valine, leucine and isoleucine degradation;Valine Leucine Isoleucine degradation (Consensus)

Recessive Scores

• pRec: 0.276

Intolerance Scores

• loftool: 0.144
• rvis_EVS: -0.86
• rvis_percentile_EVS: 10.85

Haploinsufficiency Scores

• pHI: 0.330
• hipred: N
• hipred_score: 0.486
• ghis: 0.559

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.961

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mccc1

Gene ontology

• Biological process: leucine catabolic process;biotin metabolic process;protein heterooligomerization
• Cellular component: 3-methylcrotonyl-CoA carboxylase complex, mitochondrial;mitochondrion;mitochondrial matrix;cytosol;methylcrotonoyl-CoA carboxylase complex
• Molecular function: biotin carboxylase activity;methylcrotonoyl-CoA carboxylase activity;protein binding;ATP binding;biotin binding;metal ion binding