Submission Details

The relationship between SCO2 and Leigh Syndrome Spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 25, 2019. SCO2 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 1999 (Papadopoulou et al 1999 PMID: 10545952) More than 33 unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting homozygous loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 5 probands with confirmed SCO2 mutations demonstrating a Leigh Syndrome Spectrum phenotype have been reported in 4 publications (PMID: 10545952, 11673586, 18924171, 20159436) to reach a case-level evidence score of 9. This gene-disease association is further supported by the function of the gene product, loss of expression in patient basal ganglia tissue, mitochondrial alterations, disrupted complex IV assembly in patient cell lines, and animal models reaching a maximum experimental score of 6 pts. The mechanism for disease is brain cytochrome oxidase deficiency. In summary, there is definitive evidence to support the relationship between SCO2 and autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association to reach a definitive classification. This classification was approved by the ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 25, 2019 (SOP Version 6).