SCO1

Inheritance Pattern: AR

Disease ID:MONDO:0033636

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0033636

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SCO1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 17, 2022. *SCO1* encodes a mitochondrial copper-binding protein, which also acts as a metallochaperone for the mtDNA encoded subunits COX1 and COX2 in Cytochrome *c* oxidase (complex IV) assembly. *SCO1* was first reported in relation to autosomal recessive mitochondrial disease in 2000 (PMID: 11013136). While various names have been given to the constellation of features seen in those with *SCO1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *SCO1* 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 six unique variants, including two frameshift truncating variants shown to undergo nonsense mediated decay, three missense variants, and one in-frame deletion, in four probands across four publications (PMIDs: 11013136, 19295170, 23878101, 31352446). *SCO1* pathogenic variants were first described in an infant with respiratory distress, metabolic acidosis, hepatic failure, and encephalopathy in the setting of profound complex IV deficiency in muscle and liver. Subsequent publications have shown expansion of the phenotypic spectrum including cardiomyopathy in one case and one case of encephalopathy and lactic acidosis without cardiac or hepatic involvement. Many cases reported to date have been fatal in the first few months of life. Of note, one report showed segregation in four affected family members (including two fetuses with isolated complex IV deficiency by chorionic villus sampling) and non-segregation in two unaffected siblings, which reached a LOD score of 2.06, which was sufficient to count in the case estimate (0.5 points; PMID:11013136). The total score for case-level data was 8.9 points, 8.4 of which was attributed to the four probands, three of which had extensive functional evidence to support the pathogenicity of their variants, including supportive respiratory chain enzyme assays, tissue copper studies, and western blots, as well as qPCR studies on cDNA. Loss-of-function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, functional alteration in patient cells, rescue in patient cells, and animal models (PMIDs: 23878101, 19295170, 28973536, 25683716). More evidence is available in the literature, but the maximum score for experimental evidence (6 points) has been reached. 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 the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 17, 2022 (SOP Version 8).

Inheritance Pattern: AR

Disease ID:MONDO:0033636

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0033636

Submitter: Labcorp Genetics (formerly Invitae)