ClinVar

Description

The p.P154L pathogenic mutation (also known as c.461C>T), located in coding exon 2 of the VHL gene, results from a C to T substitution at nucleotide position 461. The proline at codon 154 is replaced by leucine, an amino acid with very few similar properties. This alteration has been reported in several affected individuals/families (Crossey PA et al. Hum Mol Genet. 1994 Aug;3(8):1303-8; Whaley JM et al. Am J Hum Genet. 1994 Dec;55(6):1092-102; Banks RE et al. Cancer Res. 2006 Feb 15;66(4):2000-11; Ong KR et al. Hum Mutat. 2007 Feb;28(2):143-9). This alteration was also reported in two family members diagnosed with renal cell carcinoma, and both tumors exhibited loss of heterozygocity for this allele (Prowse AH et al. Am J Hum Genet. 1997 Apr;60(4):765-71). Truncation experiments suggest that this region is critical for p53 binding (Roe JS et al. Mol Cell. 2006 May 5;22(3):395-405). Functional analysis of this variant showed restored FGFR1 internalization and Elongin C binding similar to the wild type allele, however HIF degradation/ubiquitination was similar to that of the null mutant (Hsu T et al. J Biol Chem. 2006 Apr 28;281(17):12069-80). Structural bioinformatics mutation analysis predicts that this variant will leave an unsatisfied hydrogen bonding partner in the main chain of pVHL and that this will significantly change the protein folding altering or preventing required protein interactions (Forman JR et al. Proteins. 2009 Oct;77(1):84-96). This variant is also referred to as p.P225L (c.674C>T) in older literature. Based on the available evidence, p.P154L is classified as a pathogenic mutation.