SCO2

Inheritance Pattern: AD

Disease ID:MONDO:0012154

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0033850

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012154

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0011451

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0015626

Submitter: ClinGen

SCO2 was first linked to Mitochondrial Complex IV Deficiency, Nuclear Type 2 in 1999. Children with these mutations presented with fatal cardioencephalomyopathy often before 2 years of age. However, in 2016 Rebelo et al. identified patients from 2 families with compound heterozygous mutations in SCO2 that associated with early-onset axonal Charcot-Marie-Tooth Type 2 (CMT2) associated with copper deficiency. Rebelo et al presented functional evidence that SCO2 and COXII expression was decreased, copper was reduced in patient fibroblasts, and complex IV activity was decreased. Barcia et al. (2019) found a family with two siblings presenting with cerebellar ataxia and progressive peripheral axonal neuropathy. Spectrophotometric analysis of respiratory chain enzymes on skeletal muscle homogenate showed isolated COX deficiency. Gangfu et al (2022) corroborated these findings in a family with two affected brothers presenting with early-onset CMT2 and a novel homozygous missense variant in SCO2. Gangfu et al. showed functional evidence that there was decreased COX activity and proteomic data displaying altered COX subunits. In total, 6 variants from 3 families were scored totaling 4.5 points of genetic evidence. In a mouse model by Yang et al (2010), decreased COX activity was observed in a SCO2 knock in and knock out mouse model. This gave only one point of evidence as the nerve was not examined. Furthermore, Rebelo et al (2016) and Jaksch et al. (2001) show that copper deficiency is a common alteration in SCO2 patients (+0.5 points). Lastly, the SCO2 gene product completes a biochemical function shared with other known CMT2 genes. ATP7A is another CMT2 gene in which recessive variants cause copper dysfunction (+0.5 points). In total, we find 8 points of evidence (5 points from genetic evidence and 3 points from functional evidence) giving SCO2 a moderate classification.

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SCO2* and *SCO2*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 7, 2024. The *SCO2* gene encodes a copper metallochaperone essential for the synthesis and maturation of cytochrome *c* oxidase subunit II (MT-CO2/COX2), and is involved in transporting copper to the Cu(A) site on MT-CO2/COX2. The *SCO2* gene was first reported in relation to autosomal recessive *SCO2*-related primary mitochondrial disease in 1999 (PMID: 10545952). *SCO2* has been associated with two disease entities to date; mitochondrial complex IV deficiency, nuclear type 2 [OMIM# 604377] and myopia 6 [OMIM# 608908]. The myopia 6 phenotype is a distinct disease entity and is outside the scope of this curation. The mitochondrial complex IV deficiency, nuclear type 2 phenotype is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *SCO2*-related primary mitochondrial disease. Of note, *SCO2* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on March 25, 2019 (SOP v6), with a final classification of Definitive. This current curation for the association with *SCO2*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 12 unique variants (eight missense, three nonsense, one frameshift) identified in 18 unrelated cases from 13 publications (PMIDs: 10545952, 11673586, 18924171, 20159436, 19879173, 33098801, 32668698, 27290639, 25058219, 29351582, 31844624, 35112411, 10749987). Disease onset is typically early in life. Clinical features in affected individuals include LSS, hypertrophic cardiomyopathy, dystonia, myopathy, and neuropathy. Complex IV deficiency was noted in several tissues in affected individuals when assessed. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 15229189), functional alteration in patient cells (PMID: 16083427), and a mouse model (PMID: 19837698). In summary, there is definitive evidence to support the relationship between *SCO2* and autosomal recessive *SCO2*-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 7, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0011451

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0011451

Submitter: G2P