Submission Details

The relationship between* CYC1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 21, 2022. The CYC1 gene encodes a subunit of complex III and plays an important role in the mitochondrial respiratory chain by transferring electrons from the Rieske iron-sulfur protein (UQCRFS1) to cytochrome c.

The CYC1 gene was first reported in relation to autosomal recessive mitochondrial disease in 2013 (PMID:23910460). While various names have been given to the constellation of features seen in those with CYC1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the CYC1 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 missense variants identified in three cases from two publications (PMIDs: 23910460, 27074787). 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 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. Individuals with CYC1-related mitochondrial disease reported in the literature had neonatal insulin-responsive hyperglycemia, stress/infection-induced metabolic acidosis, and hyperammonemia with or without hepatic failure (PMID: 27074787). A fourth case was reported with a homozygous missense variant in CYC1, and this individual had recurrent optic neuritis. However, this case was not included for scoring in this gene-disease curation as this individual had a markedly different phenotype to that reported in other affected individuals with CYC1 variants and there was no evidence of complex III deficiency and/or other evidence to support the impact of the variant (PMID: 34252606). This gene-disease association is also supported by known biochemical function, functional alteration in patient cells, and rescue models in patient cells (PMIDs: 23910460, 28844695).

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 March 21, 2022 (SOP Version 8).