Submission Details

The relationship between MT-TY and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 16, 2023. MT-TY encodes the mitochondrial transfer RNA (tRNA) for tyrosine. 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-TY was first reported in relation to maternally-inherited primary mitochondrial disease in 2000 (PMID:11071502), in a 36-year-old woman with exercise intolerance, mild muscle weakness, and ptosis. While various names could be given to the constellation of features seen in those with MT-TY-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TY 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 seven unique variants including two deletions (m.5835G>A, m.5860_5861del, m.5865T>C, m.5874T>C, m.5877C>T, m.5888del, m.5889A>G) observed in seven probands across seven publications (PMIDs: 11071502, 11756614, 11594340, 33279411, 30643656, 32684384, 32485333). Of note, the m.5843A>G variant was excluded from scoring given its population frequency and lack of impact on tyrosylation (PMIDs: 14598342, 18268021). Age of onset in affected individuals is variable and clinical features seen include myopathy with or without ophthalmoplegia. There is at least one case report with a more severe phenotype with neuropathy, ataxia, seizures, myoclonus, sensorineural hearing loss, and pigmentary retinopathy (PMID:33279411). Muscle biopsy in affected individuals has shown COX-negative and ragged red fibers, with variable mitochondrial respiratory chain enzyme deficiencies. The variants in affected individuals are often present at highest heteroplasmy levels in muscle and may be undetectable in other tissues such as blood and buccal tissue. Multiple single fiber studies were performed in these patients and supportive of variant pathogenicity (PMIDs: 11071502, 11756614, 32684384). 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, functional alteration in patient cells and non-patient cells, and models (PMIDs: 30030363, 18268021, 32684384, 3295486, 19492087).

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 February 16, 2023 (SOP Version 9).