MT-TG

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MT-TG* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 7, 2022. The *MT-TG* gene encodes the mitochondrial transfer RNA (tRNA) for glycine, which is located from m.9991-10058 on the heavy strand of 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-TG* was first reported in relation to maternally inherited primary mitochondrial disease in 1994 in a family with maternally inherited hypertrophic cardiomyopathy (PMID: 8079988). While various names have been given to the constellation of features seen in those with *MT-TG*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT-TG* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting the gene-disease relationship between *MT-TG* and primary mitochondrial disease includes case-level data and experimental data. This curation includes four variants (m.9997T>C, m.10000G>A, m.10010T>C, m.10038G>A) observed in six probands in six publications (PMIDs: 8079988, 9199564, 11971101, 16120360, 32337339, 35432167). Segregation evidence is scored as case-level data according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. Age of onset in affected individuals varied from early in life to the 20s. Clinical features included hypertrophic cardiomyopathy, myopathy, peripheral neuropathy, exercise intolerance, headache, seizures, ataxia, dystonic posturing, optic atrophy, retinal dystrophy, cataracts, and hearing loss. Progressive atrophy and bilateral basal ganglia calcifications were seen on brain imaging. Tissue biopsies identified ragged red fibers and decreased COX histochemical activity in muscle. Lab values showed increased blood lactate and increased creatine kinase. Decreased activities of complexes I, III, and IV were observed in biopsied muscle. Heteroplasmy levels of the variants in affected individuals ranged from 88-92% in muscle, 40-56% in urine, undetectable to 32% in blood, 27% in buccal samples, and was undetectable when assessed in fibroblasts. Single fiber testing and cybrid analysis further supported variant pathogenicity. This gene-disease relationship is also supported by known biochemical function and functional alterations in patient cells (in vitro functional assays demonstrated reduced rates of mitochondrial translation as a result of variants in *MT-TG*; PMID: 10090480). In summary, there is moderate evidence to support the relationship between *MT-TG* and maternally inherited primary mitochondrial disease. 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 November 7, 2022 (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.