The relationship between SDHC and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 7, 2022. The SDHC gene encodes the succinate dehydrogenase complex iron sulphur subunit C. Defects of this protein lead to complex II deficiency.
This gene has also been implicated in autosomal dominant hereditary paraganglioma. This gene disease relationship has been assessed separately (https://search.clinicalgenome.org/kb/genes/HGNC:10682). However, after extensive literature review, no cases have been reported to have features consistent with primary mitochondrial disease. There is one mouse model (PMID: 31469588) with features that resemble primary mitochondrial disease, including lactic acidosis, hypoglycemia, circulating insulin decrease, weight loss, elevated CK, decreased muscle function, decline in activity, and, most importantly, protection from death by hypoxic conditioning. However, brain pathology did not reveal Leigh syndrome features and there was no direct biochemical evidence of complex II deficiency.
In summary, there is no evidence for a causal role for SDHC variants in primary mitochondrial disease. This gene-disease association is not supported by experimental evidence and no reports have directly implicated the gene in individuals with primary mitochondrial disease to date. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 7, 2022 (SOP Version 8).
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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