MT-TV

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MT-TV* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 3, 2023. The *MT-TV* gene encodes the mitochondrial transfer RNA (tRNA) for valine. 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 and thus impaired OXPHOS enzyme activities. *MT-TV* was first reported in relation to maternally-inherited primary mitochondrial disease in 1998 in an individual with progressive hearing and vision loss, cognitive impairment, and muscle weakness (PMID: 9450773). Other associated features have been reported over time. While various names could be given to the constellation of features seen in those with *MT-TV*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT-TV* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *MT-TV* 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 Moderate. This current curation for the association with primary mitochondrial disease includes cases with LSS. Evidence supporting the gene-disease relationship between *MT-TV* and primary mitochondrial disease includes case-level data and experimental data. This curation includes three variants (m.1606G>A, m.1630A>G, m.1644G>A) in eight probands in six publications (PMIDs: 9450773, 12056939, 19252805, 15320572, 18314141, 24691472). Single fiber testing and cybrid analyses further supported the pathogenicity of several of these variants (PMIDs: 24691472, 9450773, 19252805). Age of onset in affected individuals ranged from childhood to adulthood. Clinical features in affected individuals included LSS, cognitive decline, fatigue, migraines, seizures, myoclonic jerks, ataxia, dystonia, dysarthria, imbalance, muscle weakness, axonal sensorimotor polyneuropathy, diabetes, gastrointestinal dysmotility, cataracts, retinitis pigmentosa, sensorineural hearing loss, and hypertrophic cardiomyopathy. Brain imaging was variable and ranged from normal to findings consistent with LSS, cerebellar and cerebral atrophy, brainstem atrophy, and basal ganglia calcifications. Muscle biopsies showed ragged red fibers, COX-deficient fibers, and normal to decreased respiratory chain enzyme activities. Metabolic laboratory investigations revealed elevated lactate. Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed (67% to homoplasmic in muscle, 70% to homoplasmic in blood, and homoplasmic in skin fibroblasts). Segregation evidence is scored as case-level data according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by known biochemical function and in vitro functional assays demonstrating altered mitochondrial function as a result of variants in *MT-TV* (PMIDs: 21986556, 33340416, 35148219). In summary, there is definitive evidence to support the relationship between *MT-TV* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and 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 on April 3, 2023.

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between *MT-TV* and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of April 14, 2021. The *MT-TV* gene encodes the mitochondrial transfer RNA (tRNA) for valine. 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 and thus impaired OXPHOS enzyme activities. The *MT-TV* gene was first reported in relation to maternally inherited Leigh syndrome spectrum in 1997 (PMID: 9270602). This curation included 3 variants in 6 cases (2 with m.1624C>T, 3 with m.1644G>T, and 1 with m.1659T>C) from 5 publications (PMIDs: 9270602, 11799391, 15465092, 23063709, 24691472). Segregation information is scored as case level evidence according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function (PMID: 27977873). In summary, there is moderate evidence to support this gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 14, 2021 (SOP Version 8).