The relationship between COX14 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 21, 2022. The COX14 gene encodes a Complex IV, or cytochrome c oxidase (COX) assembly factor and is also involved in translation of MT-CO1, the gene encoding the COX1 subunit of the enzyme.
The COX14 gene has been reported in relation to autosomal recessive primary mitochondrial disease in a single family in a single publication in 2012 (PMID: 22243966). While various names have been given to the constellation of features seen in those with COX14-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the COX14 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. While segregation data were considered, the LOD score (1.68) did not meet criteria to be scored per the ClinGen Gene Curation SOP V8 (PMID: 22243966). This curation included one homozygous variant identified in one proband in one publication (PMID: 22243966). Affected individuals in this family had a severe lactic acidosis and died shortly after birth. Loss of function is suspected to be the mechanism of disease. This gene-disease association is also supported by known biochemical function, functional alteration in patient cells, functional alteration in non-patient cells, and rescue in patient cells (PMID: 22243966).
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 March 21, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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