Submission Details

The relationship between MT-TL1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 17, 2023. The MT-TL1 gene encodes a mitochondrial tRNA for leucine (UUR), which is located from m.3230-3304 on the heavy strand of the mitochondrial DNA (mtDNA). 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, resulting in impaired OXPHOS enzyme activities.

While various names have been given to the constellation of features seen in those with MT-TL1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TL1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, MT-TL1 was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on May 17, 2021 (SOP v8), with a final classification of limited. This current curation for the association with primary mitochondrial disease includes cases with LSS.

MT-TL1 was first reported in association with maternally inherited primary mitochondrial disease in 1990 (PMIDs: 2268345, 2102678) in individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Subsequent publications have shown a spectrum of phenotypes in those with MT-TL1 – related primary mitochondrial disease including MELAS, myoclonus epilepsy, ragged red fibers (MERRF), Leigh syndrome spectrum, progressive external ophthalmoplegia (PEO), and maternally inherited deafness and diabetes (MIDD), as well as myopathy, hypertrophic cardiomyopathy, and renal disease (PMIDs: 9323566, 12221518, 20471262, 23220830, 23273904, 24338029, 23582502, 11271374, 23258140).

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 7 unique recurrent missense variants, all of which have been reviewed by the Mitochondrial Disease Variant Curation Expert Panel (VCEP) and classified as pathogenic or likely pathogenic (m.3243A>G, m.3243A>T, m.3256C>T, m.3258T>C, m.3291T>C, m.3302 A>G, m.3303C>T). There is a substantial amount of functional evidence for these variants, including numerous cybrid analyses, single fiber studies, and respiratory chain analyses showing clear evidence of OXPHOS defects (PMIDs: 11733109, 10672326, 20471262, 23273904, 17130166, 11271374, 30404982, 12798797, 8254046). Heteroplasmy levels of MT-TL1 variants can be variable in tissues from the same individual. In general, variants tend to be lower in tissues such as blood, saliva, and buccal swab and urine and muscle heteroplasmy levels tend to be higher, highlighting the importance of testing multiple tissues to fully assess variant heteroplasmy levels in an affected individual. Individuals with mitochondrial myopathy have been reported with heteroplasmy levels as low as 30% in muscle (PMID: 23220830). In summary, this curation included 8 probands from 8 publications (PMIDs: 9323566, 12221518, 20471262, 23220830, 23273904, 24338029, 23582502, 11271374), however, there are hundreds of individuals reported in the literature with the m.3243A>G variant alone (PMID: 29560378).

This gene-disease association is also supported by functional implication given protein interaction with the multitude of other mitochondrial translation proteins linked to primary mitochondrial disease and compelling single fiber data from patients’ cells (not included in case scoring) showing mitochondrial dysfunction, and a mouse model of the m.3302A>G variant (PMIDs: 8254046, 12798797, 35998911, 30030363).

In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 17, 2023 (SOP Version 9).