Submission Details

The relationship between MT-TL2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 5, 2023. The MT-TL2 gene encodes a mitochondrial tRNA for leucine (CUN). 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.

MT-TL2 was first reported in association with maternally inherited primary mitochondrial disease in 1996 (PMID: 8923013) in an individual with chronic progressive external ophthalmoplegia (CPEO), myopathy, pigmentary retinopathy, and sensorineural hearing loss. Subsequent publications have shown a spectrum of phenotypes in those with MT-TL2 – related primary mitochondrial disease including myopathy, exercise intolerance, and peripheral neuropathy (PMIDs: 8923013, 12398839, 19718780, 18977334, 21819490, 15649400, 15591266, 23847141, 20022607, 29052516). While various names have been given to the constellation of features seen in those with MT-TL2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TL2 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, MT-TL2 was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on April 14, 2021 (SOP v8), with a final classification of disputed, as the reported cases at the time may have had brain appearances similar to those observed in LSS, however evidence of variant pathogenicity was insufficient. Additionally, there was no experimental evidence to support that gene-disease relationship at that time.

Evidence supporting the gene-disease relationship between MT-TL2 and primary mitochondrial disease includes case-level data and experimental data. This curation included four unique recurrent missense variants present in 14 probands from 10 publications (PMIDs: 8923013, 12398839, 19718780, 18977334, 21819490, 15649400, 15591266, 23847141, 20022607, 29052516). Each of these variants had been reviewed by the Mitochondrial Disease Variant Curation Expert Panel (VCEP) and classified as likely pathogenic or of uncertain significance (m.12276G>A, m.12294G>A, m.12315G>A, m.12316G>A). There is a substantial amount of functional evidence for these variants, including numerous single fiber studies, and respiratory chain analyses showing clear evidence of OXPHOS defects (PMIDs: 8923013, 19718780, 18977334, 21819490, 15649400, 20022607, 23847141, 29052516). Heteroplasmy levels of MT-TL2 variants can be variable in tissues from the same individual. In general, variants tend to be present at lower levels 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. Of note, individuals with mitochondrial myopathy have been reported with heteroplasmy levels as low as 18% in muscle (PMID: 15591266).

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 (PMID: 27977873).

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 June 5, 2023 (SOP Version 9).