The VHL gene is associated with the autosomal dominant cancer syndrome von Hippel Lindau disease which includes retinal hemangiomas, cerebellar and spinal hemangioblastomas, renal cell carcinoma and pheochromocytomas https://www.ncbi.nlm.nih.gov/books/NBK1463/. . Following multiple reports of segregation and linkage analysis from large pedigrees of VHL-affected families (PMID: 6582782, PMID: 2642584, PMID: 1982450, PMID: 1680799), the VHL gene was identified by Latif et al in 1993 (PMID: 8493574). Numerous variants have been reported in VHL in relation to the development of von Hippel Lindau disease, and this gene curation relies on a cohort of 114 cases with 12 unique VHL truncating and missense variants from Chen et al 1995 (PMID:7728151) . Although the present curation does not distinguish between VHL Type 1 and Type 2, generally, truncating and grossly damaging missense are associated with VHL Type 1 while less damaging missense are associated with VHL Type 2. The present curation does not include Chuvash Polycythemia or associated variants. Other databases describing germline VHL variants include: Clinical Interpretations of Variants in Cancer (https://civicdb.org), VHLdb (http://vhldb.bio.unipd.it/home), and large compendiums of genetic variants (PMID: 20151405). There is extensive genetic evidence supporting this gene-disease relationship including both case-level and familial data. The VHL gene is a tumor-suppressor with a wide variety of cellular functions (PMID: 25533676), most notably in regulation of Hypoxia Inducible Factor A (HIFa) through binding to hydroxylated HIFa, which induces subsequent ubiquitination and proteasomal degradation (PMID: 25533676). To bind hydroxylated HIFa, VHL is assembled into a complex with CUL2, RBX1 and Elongin B and C (VCB complex). The molecular mechanism of VHL dysfunction in von Hippel Lindau disease involves mutations which result in absent or reduced assembly of the VCB complex, or absent/reduced binding of the VCB complex (VHL) to HIFa. This gene-disease relationship is supported experimentally by expression studies, biochemical function, functional alterations and animal models. In summary, VHL is definitively associated with the autosomal autosomal dominant von Hippel Lindau syndrome. This has been demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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