The relationship between COX6B1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 21, 2022. The COX6B1 gene encodes cytochrome c oxidase (complex IV) subunit 6B1. Defects of this protein lead to complex IV deficiency.
The COX6B1 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2008 (PMID: 18499082). While various names have been given to the constellation of features seen in those with COX6B1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the COX6B1 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 three unique variants, each present in the homozygous state in three cases from three publications (PMIDs: 18499082, 22277967, 24781756). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, functional alteration in non-patient cells, rescue in patient cells, and model systems (PMIDs: 18499082, 24781756, 34937540).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by 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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