Submission Details

The relationship between MT-TP and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 19, 2022. MT-TP encodes the mitochondrial tRNA for proline. 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-TP was first reported in relation to maternally-inherited primary mitochondrial disease in 1993 in a female proband with proximal myopathy and weakness with elevated serum lactate (PMIDs: 7689388, 8190311). While various names could be given to the constellation of features seen in those with MT-TP-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TP 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 six unique variants (m.15958A>T, m.15967G>A, m.15975C>T, m.15990C>T, m.16002T>C, m.16023G>A; of note m.15990C>T, m.15975C>T, and m.16002T>C have been reported in more than one proband) observed in nine probands across nine publications (PMIDs: 7689388, 11196116, 19223931, 23696415, 19273760, 27536729, 27816331, 32305257, 32419253). Age of onset of affected individual is variable. Clinical features reported include myopathy, chronic progressive external ophthalmoplegia (CPEO), retinal dystrophy, and lactic acidosis. Muscle biopsy often shows classic findings of mitochondrial myopathy with COX-negative and ragged red fibers. Respiratory chain enzyme deficiencies may also be observed in muscle biopsies. The pathogenic variants were present at high levels of heteroplasmy in muscle tissue and, frequently, other tissues such as blood, saliva, buccal samples, urine, and fibroblasts harbored the variant at substantially lower heteroplasmy levels, including being undetectable. Affected individuals have been reported with heteroplasmy levels as low as 25-40% in muscle tissue. Single fiber studies were performed in several probands further supporting variant pathogenicity (PMIDs: 7689388, 32305257, 19273760, 27536729). 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 and compelling single fiber data from patients’ cells (not included in case scoring; PMIDs: 30030363, 27536729).

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 December 19, 2022 (SOP Version 9).