Submission Details

The relationship between MAT1A and methionine adenosyltransferase deficiency was evaluated using the ClinGen Clinical Validity Framework as of August 15th, 2019. Methionine adenosyltransferase catalyzes a two-step reaction in which the adenosyl group of ATP is transferred to methionine to form S-adenosylmethionine, a methyl donor, and tripolyphosphate. Individuals with methionine adenosyltransferase deficiency present with persistently elevated levels of plasma methionine. Most patients with this condition are identified with hypermethioninemia on newborn screening. Follow up testing reveals normal or mildly elevated homocysteine, ruling out homocystinuria, and normal tyrosine, ruling out tyrosinemia. Most individuals with methionine adenosyltransferase deficiency have no symptoms, although some patients have developed demyelination of the brain and other abnormalities (Nashabat et al, 2018, PMID 29440907). Biallelic variants in MAT1A causing methionine adenosyltransferase were first reported by Ubagai et al in 1995 (PMID 7560086). Data from 17 patients who are homozygous or compound heterozygous for MAT1A variants were curated, including 21 unique variants (missense, nonsense, frameshift, and splicing) from 8 publications (Ubagai et al, 1995, PMID 7560086; Chamberlin et al, 1996, PMID 8770875; Hazelwood et al, 1998, PMID 9482646; Linneback et al, 2005, PMID 16435220; Fernández-Irigoyen et al, 2010, PMID 20675163; Hirabayashi et al, 2013, PMID 23973726; Nagao et al, 2013, PMID 24231718; Kim et al, 2016, PMID 26933843). More data are available but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of methionine adenosyltransferase, which is consistent with the finding of persistently elevated methionine levels in patients with this condition (Cantoni, 1951, PMID 14832292; Mudd, 1962, PMID 14476836), and a knock out mouse model (Lu et al, 2001; PMID 11320206). In summary, MAT1A is definitively associated with autosomal recessive methionine adenosyltransferase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on September 13th, 2019. Of note, while most individuals who are heterozygous for variants causing autosomal recessive methionine adenosyltransferase deficiency have normal methionine levels, some variants are reported to cause hypermethioninemia in the heterozygous state, although the level of methionine is lower than that seen in individuals who have biallelic variants in MAT1A (Kim et al, 2016; PMID 26933843). The most commonly reported variant, c.791G>A (p.Arg264His), has been shown to segregate with hypermethioninemia is an autosomal dominant manner. This variant disrupts the normal dimerization of methionine adenosyltransferase and therefore appears to act as a dominant-negative (Chamberlin et al, 1997, PMID 9042912).