ClinVar

Description

The p.F119L pathogenic mutation (also known as c.357C>G), located in coding exon 2 of the VHL gene, results from a C to G substitution at nucleotide position 357. The phenylalanine at codon 119 is replaced by leucine, an amino acid with highly similar properties. In one study, in silico, in vitro, and bacterial assays showed that the p.F119L alteration results in loss of folding, stability, and function of the VHL protein (Shmueli MD et al. PLoS ONE. 2013 Jun;8:e66333). Based on internal structural assessment, this alteration results in critical structural destabilization of the core of the protein (Van Molle I et al. Chem. Biol. 2012 Oct;19:1300-12). This mutation has been identified in multiple individuals/families with a clinical diagnosis or suspicion of von-Hippel-Lindau (VHL) syndrome (Zbar B et al. Hum. Mutat. 1996;8:348-57; Bausch B et al. J Transl Med Epidemiol. 2014 2(1):1019; Klein B et al. Hum. Genet. 2001 May;108:376-84, Ambry internal data). It has also been reported in a patient with non-syndromic pheochromocytoma (Neumann HP et al. N. Engl. J. Med. 2002 May;346:1459-66) and a patient with bilateral adrenal phenochromocytoma and a carotid paraganglioma (Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun;94:1938-44). Of note, this alteration is also designated as 570C>G in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In silico splice site analysis predicts that this alteration may weaken the native splice site acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.