The relationship between MTFMT and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 26, 2020. The MTFMT gene encodes mitochondrial methionyl-tRNA formyltransferase which catalyzes the formylation of the mitochondrial methionine tRNA (Met-tRNAMet). This formylation is required for the initiation of translation and elongation of mitochondrial protein synthesis.
The MTFMT gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2011 (PMID: 21907147). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six variants identified in ten cases in four publications (PMIDs: 21907147, 23499752, 30911575, 24461907). Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, functional alteration in non-patient cells, and rescue in patient cells (PMIDs: 29980628, 30087118, 21907147).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 26, 2020 (SOP Version 7).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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