Submission Details

The relationship between MMAB and methylmalonic acidemia was evaluated using the ClinGen Clinical Validity Framework as of January 22, 2021. Loss of function of the MMAB gene product, ATP:cob(I)alamin adenosyltransferase (ATR), has been reported to methylmalonic acidemia (MMA) type CblB based on complementation studies. The severe, early-onset form of this condition presents with neonatal ketoacidosis, lethargy, failure to thrive and encephalopathy. Patients with a milder form are usually diagnosed during infancy and have less severe neurological symptoms (Brasil et al, 2015). While patients with MMA due to variants in MMAA (type CblA) are responsive to Vitamin B12, only rare individuals with type CblB are responsive to treatment with Vitamin B12 (Hörster, et al, 2007, PMID 17597648; Manoli et al, 2016, PMID 20301409). Biallelic variants in MMAB were first reported in humans with methylmalonic acidemia (MMA) in 2002 (Dobson et al, PMID 12471062). Since then, over 30 different variants have been associated with the condition (Brasil et al, 2015, PMID 24813872; https://databases.lovd.nl/shared/variants/MMAB/unique ). Evidence supporting this gene-disease relationship includes case-level and experimental data. Ten unique variants (nonsense, frameshift, splice site, missense) from 8 probands from 3 publications were curated (Dobson et al, 2002, PMID 12471062; Lerner-Ellis et al, 2006, PMID 16410054; Brasil et al, 2015, PMID 24813872). Further evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. The gene-disease relationship is also supported by the biochemical function of ATR, which converts reduced cob(I)alamin to adenosylcobalamin (AdoCbl), the cofactor of methylmalonyl-CoA mutase (MUT) (Leal et al, 2003, PMID 12514191; Yamanishi et al, 2005, PMID 15950874; Mera and Escalante-Semerena, 2010, PMID 20677021). MUT catalyzes the reversible rearrangement of methylmalonyl-CoA to succinyl-CoA during the catabolism of branched-chain amino acids, odd-chain fatty acids and cholesterol. Lack of AdoCbl is therefore expected to result in reduced MUT activity, and methylmalonic acidemia. Of note, other defects in cobalamin metabolism can affect the activity of methionine synthase in addition to MUT, thus causing both homocystinuria and MMA. The relationship between MMAB and MMA is also supported by functional alteration studies. Mutagenesis of human MMAB and expression of the variants in a bacterial system revealed missense variants that reduce ATR activity and AdoCbl binding (Fan and Bobik, 2008, PMID, 18251506). In summary, MMAB is definitively associated with methylmalonic acidemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.