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.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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