Submission Details

The relationship between MTR and methylcobalamin deficiency type cblG, an autosomal recessive disorder of cobalamin metabolism, was evaluated using the ClinGen Clinical Validity Framework as of April 30, 2021. MTR encodes methionine synthase (5-methyltetrahydrofolate-homocystine S-methyltransferase) which catalyzes the transmethylation of homocysteine by 5-methyltetrahydrofolate to give methionine and tetrahydrofolate. Individuals with bilalleic variants in MTR, resulting in loss of function of methionine synthase, usually present in infancy with hematological abnormalities, muscular hypotonia, and neurocognitive impairment. Some patients present with impaired consciousness, seizures, or visual impairment (Huemer et al, 2015, PMID 25526710; Sloan et al, 2018, PMID 20301503). Variants in MTR were first reported in patients with methylcobalamin deficiency type cblG in 1996 (Gulati et al, PMID 8968736; Leclerc et al, PMID 8968737). Data from 23 probands, who are homozygous or compound heterozygous for MTR variants, were curated. This curation includes 30 unique variants (missense, frameshift, nonsense, splice site, intronic) from 8 publications (Gulati et al, 1996, PMID 8968736; Wilson et al, 1998, PMID 9683607; Watkins et al, 2002, PMID 12068375; Fofou-Caillierez et al, 2013, PMID 23825108; Huemer et al, 2015, PMID 25526710; Vaisbich et al, 2017, PMID 28210839; Kasapkara et al, 2019, PMID 31951343; Liu et al, 2019, PMID 30651581). One variant, p.Pro1173Leu, was found in 66% of alleles in 24 patients in one study, with evidence showing that the variant has arisen more than once (PMID: 12068375). 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 MTR, methionine synthase, which is consistent with the biochemical features in patients with methylcobalamin deficiency type cblG (Loughlin et al, 1964, PMID 14216440; Banerjee et al, 1990, PMID 2407589; Watkins et al, 2011, PMID 21312325); evidence supporting interaction with other proteins involved in cobalamin metabolism and associated with homocystinuria when deficient, including MMACHC, MMADHC, and MTRR (Fofou-Caillierez et al, 2013, PMID 23825108; Bassila et al, 2017, PMID 27771510), and the findings in an Mtr knock-out mouse model (Swanson et al, PMID 11158293) In summary, MTR is definitively associated with methylcobalamin deficiency type cblG. 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.