Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] are associated with an increased risk of multiple paragangliomas and pheochromocytomas tumors within multiple organ systems transmitted in autosomal dominant inheritance. The molecular mechanism is loss of function in one of the 4 genes comprising the succinate dehydrogenase and SDHAF gene for flavination of SDHA, as well as stabilization of the SDH complex. SDHC encodes one of the 4 subunits of SDH (succinate dehydrogenase), one of the two small integral membrane proteins in the mitochondrial complex II. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, this is a lumping Curation for SDHC and SDHC associated Hereditary Paraganglioma-Pheochromocytoma syndromes (PGL/PCC) including autosomal dominant inherited Paraganglioma 3 (MIM: 605373) and Gastrointestinal stromal tumor (MIM: 606764). SDHC was first reported in relation to PGL/PCC in 2000 [Niemann and Muller et al., PMID: 11062460]. Three nonsense, two initiation codon, three missense, one splicing and one deletion variants are included in this curation [PMID: 11062460, 15342702, 29386252 and 16405730]. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by experimental evidence. Absent expression of SDHB, the iron protein, catalytic component of mitochondrial complex II were reported in 5 PGL/PCC patients carrying SDHC germline variants [PMIDs: 19576851 and 20236688]. Loss of the complex II SDH (succinate dehydrogenase) and SQR (succinate coenzyme Q oxidoreductase) enzyme activities were shown in Hela cells and Chinese hamster B9 cells transfected with two SDHC mutants, His127Ala and His127Tyr. The absence of SDH and SDR activities in SDHC targeted shRNA Hela and B9 cells can be rescued by wt SDHC construct, but not by the constructs of the two SDHC mutants [PMID: 19332149]. Knockout mouse homolog of human SDHC is homozygous-lethal [PubMed: 27626380]. In summary, the SDHC gene is definitely associated with autosomal dominant PGL/PCC syndrome. This has been repeatedly demonstrated in both the genetic, and experimental, biochemical and functional studies, and has been upheld over time.
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