COA3

Inheritance Pattern: Unknown

Disease ID:MONDO:0033649

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COA3* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 15, 2022. The *COA3* gene encodes cytochrome c oxidase assembly factor 3, a mitochondrial respiratory chain complex IV assembly factor important early in the complex IV assembly process. The *COA3* gene has only been reported in relation to autosomal recessive primary mitochondrial disease once in 2015 (PMID: 25604084). The *COA3* 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 compound heterozygous variants (one missense, one frameshift) identified in one proband from one publication (PMID: 25604084). Age of onset in this individual was early childhood and she was 34 years old at the time of this report. She had developmental delay, exercise intolerance, short stature, cognitive impairment, dysmorphic features (epicanthal folds, deep-set eyes), and sensorimotor polyneuropathy (demyelinating with severe axonal loss). Muscle biopsy showed complete absence of COX staining and complex IV activity was 17% of lowest control. Fibroblast testing showed complex IV activity was 65% of lowest control and a reduction in amount of fully assembled COX on BN-PAGE was seen, together with decreased steady state level of COA3 and COX1 on immunoblot and a decrease in COX1 synthesis assessed by pulse labelling. Imaging was not reported, and she had mildly elevated lactate level. The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function (complex IV activity) shared with other genes associated with primary mitochondrial disease, functional alteration in non-patient cells, rescue in patient cells, and model systems (PMIDs: 25604084, 23260140, 22610097, 23362268). 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/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 15, 2022 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0009068

Submitter: Orphanet