BackgroundTraditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHBvariants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHDvariants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for SDHDvariants. In the present study we zoom in on the genotype-phenotype associations of SDHBgene variants, considering the impact of individual gene variants on disease risk and risk of malignancy.MethodsWe analysed two large independent data sets, including a total of 448 patients with PPGL and HNPGL, and studied the association of missense or truncating SDHBvariants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis.ResultsCompared with missense variants, truncating SDHBvariants were significantly and consistently more common in patients with PPGL, by a 20 percentage point margin. Malignancy was also significantly more common in truncating versus missense variant carriers. No overall differences in age of PPGL onset were noted between carriers of the two variant types, although some individual variants may differ in certain cases. Missense variants were marginally over-represented among patients with HNPGL, but the difference was not statistically significant.ConclusionSDHBtruncating variants convey an elevated risk for development of both PPGL and malignancy compared with missense variants. These results further support earlier robust associations between truncating variants and PPGL, and also suggest that the two variant types differ in their impact on complex II function, with PPGL/HNPGL tissues displaying differing sensitivities to changes in complex II function.