Methylcrotonyl-CoA carboxylase deficiency: genes and variants

Genes linked to Methylcrotonyl-CoA carboxylase deficiency

• MCCC2: Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial

  It partners with MCCC1 to catalyze an essential carboxylation step in mitochondrial leucine catabolism. Biallelic pathogenic variants cause 3-methylcrotonyl-CoA carboxylase deficiency, which can produce hypoglycemia, acidosis, neurologic symptoms, or remain clinically mild.

  23 disease-causing and 4 uncertain variants in MCCC2 are linked to Methylcrotonyl-CoA carboxylase deficiency.

• MCCC1: Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial

  It provides one subunit of mitochondrial methylcrotonyl-CoA carboxylase, an enzyme required for leucine degradation. Biallelic loss-of-function variants cause 3-methylcrotonyl-CoA carboxylase deficiency, with clinical severity ranging from asymptomatic biochemical abnormalities to metabolic decompensation.

  7 disease-causing and 3 uncertain variants in MCCC1 are linked to Methylcrotonyl-CoA carboxylase deficiency.

Known disease-causing variants in Methylcrotonyl-CoA carboxylase deficiency

Which prediction tools work for Methylcrotonyl-CoA carboxylase deficiency

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 96 out of 100
• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 88 out of 100
• phyloP: 78 out of 100

Same protein, different disease

• 3-methylcrotonyl-CoA carboxylase 2 deficiency is also caused by MCCC2 variants; they fall partly in the same places as the Methylcrotonyl-CoA carboxylase deficiency variants (46 disease-causing).
• 3-methylcrotonyl-CoA carboxylase 1 deficiency is also caused by MCCC1 variants; they fall mostly in different places as the Methylcrotonyl-CoA carboxylase deficiency variants (21 disease-causing).

Diseases related to Methylcrotonyl-CoA carboxylase deficiency

• 3-methylcrotonyl-CoA carboxylase 2 deficiency, also linked to MCCC2
• 3-methylcrotonyl-CoA carboxylase 1 deficiency, also linked to MCCC1

Frequently asked questions

Which genes are linked to Methylcrotonyl-CoA carboxylase deficiency?

In CATVariant, Methylcrotonyl-CoA carboxylase deficiency is linked to 2 analyzed proteins: MCCC2 (Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial) and MCCC1 (Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial).

How many genetic variants are linked to Methylcrotonyl-CoA carboxylase deficiency?

37 variants: 30 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 7 are of uncertain significance or have conflicting reports.

Which uncertain variants in Methylcrotonyl-CoA carboxylase deficiency look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Methylcrotonyl-CoA carboxylase deficiency?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 28 disease-causing and 18 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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