Submission Details

The relationship between MUT and methylmalonic academi¬a due to methylmalonyl-CoA deficiency, an autosomal recessive disorder of propionyl-CoA metabolism, was evaluated using the ClinGen Clinical Validity Framework as of April 25th, 2019. Methlmalonyl-CoA mutase (MCM) is a mitochondrial enzyme that catalyzes the isomerization of L-methylmalonyl-CoA to succinyl-CoA using cobalamin as a cofactor. This is a key reaction in propionyl-CoA metabolism. Variants in MCM cause the mut type of methylmalonic aciduria, including mut0 (complete deficiency) and mut- (partical deficiency). Variants in MUT causing MMA were first reported by Ledley et al in 1990 (PMID 1970180). Since then, over 250 MUT variants have been reported. Data from 14 patients with 18 unique variants (missense, nonsense, frameshift, and splicing) from 5 publications were curated (Ledley et al, 1990, PMID 1970180; Acquaviva et al, 2005, PMID 15643616; Han et al, 2015, PMID 26454439; Chu et al, 2016, PMID 27233228; Keyfi et al, 2016, PMID 26449400). This gene-disease relationship is supported by the biochemical function of methylmalonyl-CoA mutase (Goodey et al, 1972, PMID 4654847), which is consistent with the elevated MMA and propionyl carnitine observed in patients with this condition; functional studies (Forney et al, 2014; PMID 25125334); mouse models (including Forney et al, PMID 27519416) and the results of gene therapy in a knockout mouse (Carrillo-Carrasco et al, 2010, PMID 20486773). This curation and includes data provided by Counsyl. In summary, MUT is definitively associated with autosomal recessive methylmalonic aciduria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation included data collected by Counsyl. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on May 9th, 2019.