Heterozygous germline loss-of-function mutations in any human SDH genes (SDHA, SDHB, SDHC, SDHD, referred to as SDHx), or the SDH complex assembly factor (SDHAF2), are associated with susceptibility to develop familial forms of aggressive malignancies with few therapeutic options and poor prognosis such as paragangliomas and pheochromocytomas, gastrointestinal stromal tumors as well as renal cell carcinoma not associated with a recognized syndrome [2–16]. The gene discussed is SDHB; the disease is hereditary clear cell renal cell carcinoma.