Synonymous but Not Silent: A Synonymous VHL Variant in Exon 2 Confers Susceptibility to Familial Pheochromocytoma and von Hippel-Lindau Disease

Shahida K. Flores, Ziming Cheng, Angela M. Jasper, Keiko Natori, Takahiro Okamoto, Akiyo Tanabe, Koro Gotoh, Hirotaka Shibata, Akihiro Sakurai, Takuya Nakai, Xiaojing Wang, Magnus Zethoven, Shiva Balachander, Yuichi Aita, William Young, Siyuan Zheng, Kazuhiro Takekoshi, Eijiro Nakamura, Richard W. Tothill, Ricardo C.T. AguiarPatricia L.M. Dahia

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Context: von Hippel-Lindau (VHL) 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 The Cancer Genome Atlas 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.

Original languageEnglish (US)
Article numberjcem_201900235
Pages (from-to)3826-3834
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Issue number9
StatePublished - Apr 11 2019

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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