The relationship between UQCRC2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 20, 2022. The UQCRC2 gene encodes a subunit of complex III (UQCRC2) of the mitochondrial respiratory chain. The UQCRC2 gene was first reported in relation to autosomal recessive mitochondrial disease in 2013 (PMID: 23281071). While various names have been given to the constellation of features seen in those with UQCRC2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the UQCRC2 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 two unique homozygous missense variants identified in three cases from three publications (PMIDs: 23281071, 28275242, 33865955). These individuals had neonatal hypoglycemia, lactic acidosis, and hepatopathy; and one individual had bilateral brainstem lesions consistent with Leigh syndrome spectrum. The Mitochondrial Disease Gene Curation Expert Panel reviewed scoring guidance for homozygous variants in cases with consanguinity and decided that no scoring alteration was needed in these three cases given (1) comprehensive analyses (exome sequencing) were performed, (2) homozygous variants are a common cause of mitochondrial disease, and (3) biochemical evidence in these cases supported a complex III defect. Segregation data are available but did not meet criteria to be considered for scoring per ClinGen Gene Curation SOP V8. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by the known biochemical function, functional alteration in patient cells, and rescue in patient cells (PMIDs: 28844695, 23281071, 28275242, 33865955). In summary, there is moderate 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 January 20, 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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.