The relationship between MT-TL1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 17, 2021. The MT-TL1 gene encodes the mitochondrial transfer RNA (tRNA) for mitochondrial tRNA for leucine (UUR). Defects of this tRNA lead to impaired mitochondrial translation, which leads to decreased synthesis of mtDNA-encoded subunits of oxidative phosphorylation (OXPHOS) complexes I, III, IV, and V and thus impaired OXPHOS enzyme activities.
The MT-TL1 gene was first reported in relation to maternally inherited Leigh syndrome spectrum in 1997 (PMID: 9323566). Of note, variants (particularly m.3243A>G) in MT-TL1 are more commonly associated with other mitochondrial disease clinical syndromes such as MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and/or MIDD (maternally inherited diabetes and deafness). Evidence supporting the relationship between MT-TL1 and Leigh syndrome spectrum includes case-level data and experimental data. This curation included one variant (m.3243A>G) in 3 cases 3 publications (PMIDs: 9323566, 23360351, 10799437). Segregation information is scored as case level evidence according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function and functional alteration in non-patient cells (PMID: 27977873, 25192935, 1732728).
In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 17, 2021 (SOP Version 8).
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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