ClinVar

Description

The p.L101R variant (also known as c.302T>G and 515T>G), located in coding exon 1 of the VHL gene, results from a T to G substitution at nucleotide position 302. The leucine at codon 101 is replaced by arginine, an amino acid with dissimilar properties. This variant has been identified in multiple VHL probands with either VHL type 1 or VHL, type unspecified (Zbar, B et al. Hum Mutat. 1996;8(4):348-57; Rocha, JC et al. J Med Genet. 2003 Mar;40(3):e31; Kim, HJ et al. Laryngoscope. 2013 Feb;123(2):477-83). In one Chinese VHL type 1 family, 2/2 affected individuals and one unaffected 8-year-old were found to carry this alteration while 6 unaffected individuals tested negative (Gao, Y et al. Chin Med J (Engl). 2013;126(19):3690-3). By estimating the change in free energy between the wild-type and mutant VHL protein using an in silico model, Gao et al. predicted that this missense alteration may lead to a reduced level of protein stability. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5126 samples (10252 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 4,300 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.