Submission Details

The relationship between MT-TT and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 17, 2023. MT-TT encodes the mitochondrial tRNA for threonine, which is located from m.15888-15953 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.

MT-TT was first reported in relation to maternally-inherited primary mitochondrial disease in 1991 (PMID: 1645537), in a girl with neonatal lactic acidosis. While various names could be given to the constellation of features seen in those with MT-TT-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TT phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants (m.15897G>A, m.15915G>A, m.15923A>G, m.15933G>A, m.15950G>A) in ten probands across ten publications (PMIDs: 32083134, 8769114, 9367299, 1645537, 8511015, 22638997, 29760464, 30236074, 28187756, 35808913). Age of onset in affected individuals varied from the neonatal period to more than 50 years. Clinical features in affected individuals included neonatal lactic acidosis; myoclonic epilepsy and ragged red fibers (MERRF); Leber Hereditary Optic Neuropathy (LHON); myopathy, seizures, migraines, pigmentary retinopathy, hearing loss, and diabetes. Brain imaging findings were variable. Muscle biopsies showed ragged red fibers and COX-deficient fibers. Labs showed elevated lactate. Heteroplasmy levels were highest in muscle when multiple tissues were assessed, and ranged from 33% to homoplasmy in muscle. The mechanism of disease appears to be loss of function. This gene-disease association is further supported by a known biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 30030363).

In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts this 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).

This gene-disease relationship was reevaluated on July 14, 2025 by this Expert Panel. As a result of this reevaluation, the classification did not change.