The relationship between SCP2 and sterol carrier protein 2 deficiency (Leukoencephalopathy with dystonia and motor neuropathy included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of January, 2020 and reviewed in March 2022 and update to SOP v9 in October 2022. SCP2 encodes two proteins, SCPx and SCP2 due to transcription initiation from two different promoters. SCPx is a peroxisome-associated thiolase involved in oxidation of branched-chain fatty acids while SCP2 is an intracellular lipid transfer protein.
SCP2 was first reported in relation to autosomal recessive sterol carrier protein 2 deficiency in 2006 (Ferdinandusse et al, PMID: 16685654). Only three loss of function variants have been reported in this gene in relation to this disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of Case Level Data (9 points): At least 3 patients from unrelated families in 4 publications have been reported with the null variants (PMID: 16685654, 26497993, 28033445, 37905191). The mechanism of disease is expected to be biallelic loss of function.
Summary of experimental data (4.5 points): This gene-disease association is supported by mouse models that recapitulate human disease (PMID: 9553048, 15574183, 17068117). The protein is localized to the peroxisomes in hepatocytes (PMID: 2925789 ) and it interacts with PEX5 and has a role in peroxisomal fatty acid metabolism (PMID: 21375735).
This gene-disease pair was originally evaluated by the Peroxisomal GCEP on Nov 4, 2022. It was re-evaluated on February 7, 2025. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of a new case and protein interaction evidence (PMIDs: 37905191, 36407094).
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).
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