Submission Details

The relationship between MTRR and methylcobalamin deficiency type cblE, an autosomal recessive disorder of cobalamin metabolism, was evaluated using the ClinGen Clinical Validity Framework as of May 4, 2021. MTRR encodes methionine synthase reductase. This enzyme reactivates methionine synthase by reductive methylation of its cobalamin cofactor. Individuals with methylcobalamin deficiency type cblE usually present early childhood with failure to thrive, megaloblastic anemia, developmental delay, and cerebral atrophy with white matter abnormalities. Biochemical characteristics include homocystinuria, hyperhomocysteinemia, and often hypomethioninemia (Zavadakova et al, 2005, PMID 15714522). Variants in MTRR were first reported in patients with methylcobalamin deficiency type cblE in 1998 (LeClerc et al, PMID 9501215). Data from 9 probands, who are homozygous or compound heterozygous for MTRR variants were curated. This curation includes 11 unique variants (missense, frameshift, nonsense, intronic) from 3 publications (Wilson et al, 1999, PMID 10484769; Zavadakova et al, 2002, PMID 12555939, Zavadakova et al, 2005, PMID 15714522). 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 the product of MTRR, methionine synthase reductase, which is consistent with the biochemical features in patients with methylcobalamin deficiency type cblE (Olteanu et al, 2001, PMID 11466310; Yamada et al, 2006, PMID 16769880; Wolthers et al, 2009, PMID 19243433; Watkins and Rosenblatt, 2012, PMID 22108709); evidence supporting interaction with other proteins involved in cobalamin metabolism and associated with homocystinuria including MMACHC and methionine synthase (Wolthers et al, 2007, PMID; 17477549; Bassila et al, 2017, PMID 27771510); rescue of MSR function in cblE cells (Zavadáková et al, 2005, PMID 15714522; Palhais et al, 2015, PMID 25878036); and the findings reported in a hypomorphic mouse model (Elmore et al, 2007, PMID 17369066). More evidence is available in the literature but the maximum score for experimental evidence (6 points) has been reached. In summary, MTRR is definitively associated with methylcobalamin deficiency type cblE. 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 July 2, 2021.