Submission Details

The relationship between MMADHC and autosomal recessive “inborn disorder of cobalamin metabolism and transport” was evaluated using the ClinGen Clinical Validity Framework as of April 13, 2021. MMADHC is involved in the intracellular conversion of cobalamin to its two coenzymes, adenosylcobalamin (AdoCbl) in mitochondria and methylcobalamin (MeCbl) in the cytoplasm, where it is involved in the metabolism of methylmalonic acid and homocysteine respectively. Dependent upon the type and location of the variant(s) within MMADHC, patients have either methylmalonic aciduria (MMA), homocystinuria (HC), or both (combined phenotype). For the purposes of this curation, these biochemical phenotypes were lumped together under an inborn disorder of cobalamin metabolism and transport. Of note, MMADHC has been reported to result in the cblD complementation group of cobalamin disorders. Biallelic variants in MMADHC were first reported in patients with cblD cobalamin disorder in 2008 (Coelho et al, 2008 PMID 18385497). Data from 11 probands who are homozygous or compound heterozygous for MMADHC variants were curated, including 14 unique variants (missense, inframe duplication, frameshift, nonsense, intronic) from three publications (Coelho et al, 2008, PMID 18385497; Miousse et al, 2009, PMID 19058814; Wang et al, 2018, PMID 30334532). More data is available in the literature but the maximum points for genetic evidence (12 points) has been reached. The gene-disease relationship is supported by the biochemical function of MMADHC, which is consistent with the biochemical features in patients with MMADHC variants (Gherasim et al, 2013, PMID 23415655; Jusufi et al, 2014, PMID 24722857), interaction of the MMADHC gene product with that of MMACHC which also causes an inborn disorder of cobalamin metabolism and transport resulting in homocystinuria and methylmalonic aciduria (Plesa et al, 2011, PMID 21071249; Froese et al, 2015, PMID 26483544), functional alterations studies in which variants from patients with cblD disorder were expressed in cblD fibroblasts showing that the type and location of the variants correlates with the biochemical phenotype (Stucki et al, 2012, PMID 22156578) and rescue studies with wild type MMADHC (Coelho et al, PMID 18385497). In summary, MMADHC is definitively associated with an inborn disorder of cobalamin metabolism and transport. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on April 30, 2021.