PURPOSE: von Hippel-Lindau (VHL) disease is a dominantly inherited, 
multisystemic tumor syndrome caused by mutations in the VHL gene. This study was 
conducted to establish genotype-phenotype correlations between the positions of 
disease-causing missense mutations and the ocular phenotypes of VHL disease.
METHODS: Participants with clinically defined VHL disease and documented 
germline missense mutations in the VHL gene were identified in a cross-sectional 
study (n=412). Statistical analysis was used to correlate the position of the 
missense mutation in either the alpha- or beta-domain of the VHL protein with 
the ocular disease phenotype.
RESULTS: Missense mutations among study participants were located in 47 of the 
213 possible codons in the VHL gene. Almost all mutations (98.5%) were located 
in one of two structural domains of the VHL protein: the alpha- and 
beta-domains. alpha-Domain mutations were significantly associated with a higher 
prevalence of retinal capillary hemangioblastomas (RCHs) compared with the 
beta-domain mutations (P=0.016). Among patients with RCHs, the prevalence of the 
lesions in the juxtapapillary position was also significantly higher in patients 
with alpha-domain mutations (P=0.0017). Conversely, beta-domain mutations 
correlated with a higher prevalence of peripherally located RCHs (P=0.0104).
CONCLUSIONS: The location of missense mutations in the VHL gene correlates 
significantly with the prevalence and phenotype of ocular disease, and as such, 
influences the risk of visual loss in affected patients. These 
genotype-phenotype correlations can assist in the prognostic counseling and 
follow-up of VHL patients and may provide a basis for molecular inferences on 
ocular VHL disease pathogenesis.