CFTR and cystic fibrosis: Similarly, two missense mutations in cis, each individually exerting a comparatively mild or no effect on the clinical phenotype, can act in concert leading to a more severe effect on the phenotype than either acting alone (e.g. CFTR Arg347His and Asp979Ala in cystic fibrosis; Clain et al. 2001 or RET Cys634Tyr and Tyr791Phe resulting in pheochromocytoma with high penetrance; Toledo et al. 2010).