A synonymous VHL variant in exon 2 confers susceptibility to familial pheochromocytoma and von Hippel-Lindau disease.

CONTEXT: von Hippel-Lindau disease, comprising renal cancer, hemangioblastoma and/or pheochromocytoma (PHEO) is caused by missense or truncating variants of the VHL tumor suppressor gene, which is involved in degradation of hypoxia inducible factors (HIFs). However, the role of synonymous VHL variants in the disease is unclear. OBJECTIVE: We evaluated a synonymous VHL variant in patients with familial PHEO or VHL disease without a detectable pathogenic VHL mutation. DESIGN: We performed genetic and transcriptional analyses of leukocytes and/or tumors from affected and unaffected individuals and evaluated VHL splicing in existing cancer databases. RESULTS: We identified a synonymous VHL variant(c.414A>G, p.Pro138Pro) as the driver event in five independent individuals/families with PHEOs or VHL syndrome. This variant promotes exon 2 skipping and, hence, abolishes expression of the full-length VHL transcript. Exon 2 spans the HIF binding domain, required for HIF degradation by VHL. Accordingly, PHEOs carrying this variant display HIF hyperactivation typical of VHL loss. Moreover, other exon 2 VHL variants from the TCGA pan-cancer datasets are biased toward expression of a VHL transcript that excludes this exon, supporting a broader impact of this spliced variant. CONCLUSION: A recurrent synonymous VHL variant (c.414A>G, p.Pro138Pro) confers susceptibility to PHEO and VHL disease through splice disruption, leading to VHL dysfunction. This finding indicates that certain synonymous VHL variants may be clinically relevant and should be considered in genetic testing and surveillance settings. The observation that other coding VHL variants can exclude exon 2 suggests that dysregulated splicing may be an underappreciated mechanism in VHL-mediated tumorigenesis.