MT-CO3

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between MT-CO3 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 24, 2021. The MT-CO3 gene encodes cytochrome c oxidase (complex IV) subunit 3. Defects of this protein lead to complex IV deficiency. The first and only report of maternally inherited Leigh syndrome spectrum related to the MT-CO3 gene was in 2000 (PMID: 11063732). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one variant (m.9537dupC) in one case from one publication (PMID: 11063732). Other variants in this gene have been related to other mitochondrial diseases outside the scope of this curation. 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 protein interaction, expression, and functional alterations in patient cells (PMIDs: 27977873, 25613900, 11063732). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 24, 2021 (SOP Version 8).

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MT-CO3* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 20, 2023. The *MT-CO3* gene encodes subunit III of cytochrome c oxidase (COX), also called complex IV of the respiratory chain, which is located from m.9207-9987 on the heavy strand of the mitochondrial DNA (mtDNA). Defects of this protein lead to complex IV deficiency. While various names have been given to the constellation of features seen in those with *MT-CO3*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT-CO3* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *MT-CO3* was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on May 24, 2021 (SOP v8), with a final classification of limited. This current curation for the association with primary mitochondrial disease includes cases with LSS. *MT-CO3* was first reported in relation to maternally-inherited primary mitochondrial disease in 1996 (PMID: 8630495), in a 15-year-old girl with a history of exercise intolerance, rhabdomyolysis, and muscle biopsy findings consistent with mitochondrial myopathy. Subsequent publications have shown three main phenotypes seen in those with *MT-CO3*-related primary mitochondrial disease: Leigh syndrome spectrum seen in one case (PMID: 11063732), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) seen in two cases (PMIDs: 33863631, 34054915), and a myopathic phenotype that often involves isolated or recurrent episodes of rhabdomyolysis in five cases (PMIDs: 8630495, 9634511, 12414820, 21163656, 16288875). Muscle biopsies in affected individuals universally showed COX-negative fibers, and 8/9 showed an isolated complex IV deficiency. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 3 unique missense variants, 3 nonsense variants, 2 frameshift variants, and 1 in-frame deletion. These variants were generally present at high levels of heteroplasmy in muscle tissue and at lower to undetectable levels in other tissues such as blood and buccal tissue, highlighting the diagnostic importance of muscle biopsy in *MT-CO3*-related primary mitochondrial disease. Single fiber studies were performed in several affected individuals and were supportive of variant pathogenicity. In summary, this curation included 8 probands reported in 9 papers from 1995-2021 (PMIDs: 11063732, 33863631, 34054915, 8630495, 9634511, 12414820, 21163656, 16288875). Notably, the m.9957T>C variant (PMID:7496173) was not included in this curation given a relatively high population frequency (0.081% in MITOMAP’s GenBank sequences and 0.028% in gnomAD v3.1.2, all homoplasmic occurrences) and given that nuclear DNA etiologies were not excluded. This gene-disease association is also supported by functional implication given protein interaction with the multitude of other COX subunits and assembly factors linked to primary mitochondrial disease and functional alteration in patient cells, including cybrid analyses (PMIDs: 10788526, 30030519, 34054915). In summary, there is definitive evidence to support the relationship between *MT-CO3* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 20, 2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0009068

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0020504

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010788

Submitter: Orphanet