ClinVar

Description

The p.L163F variant (also known as c.487C>T), located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 487. The leucine at codon 163 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with a personal and/or family history of VHL-associated disease (Tong AL et al. Ann. N. Y. Acad. Sci., 2006 Aug;1073:203-7; Pandit R et al. Eur. J. Endocrinol., 2016 12;175:X3; Lomte N et al. Fam Cancer, 2018 Jul;17:441-449; Goldstein M et al. AACE Clin Case Rep, 2020 May;6:e193-e196; Ambry internal data). Further, alterations at the same codon, p.L163P and p.L163R, have been reported in individuals with presumed sporadic Von Hippel-Lindau (VHL), as well as isolated pheochromocytoma (Cho HJ et al, J. Korean Med. Sci. 2009 Feb; 24(1):77-83; Sansó G et al, Am. J. Hypertens. 2004 Dec; 17(12 Pt 1):1107-11). Based on internal structural assessment, this alteration destabilizes the VHL elongin binding domain (Van Molle I et al. Chem. Biol., 2012 Oct;19:1300-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.