Is P25L a "Real" VHL mutation?

Background: The von Hippel-Lindau (VHL) gene has two translational initiati on sites separated by 53 codons. Both proteins have been detected in cells and have equivalent activity. A mutation in the first 53 codons of the open reading frame has no effect on the structure of the smaller protein. As ex pected, the vast majority of VHL mutations are downstream of the second ini tiation site and alter both proteins. However, several candidate mutations have been found in the first 53 codons, including a substitution of leucine for proline at position 25 (P25L) of the larger protein. Methods and Results: DNA sequence analysis showed two VHL gene mutations, P 25L and P86R, in an individual with a clinical diagnosis of VHL disease. Bo th mutations have been reported previously. P25L alters only the upstream p rotein, whereas P86R alters both VHL proteins. Based on the positions of th e mutations, P86R is more likely to be pathogenically significant than the P25L mutation. A survey of anonymized DNAs for P25L, using allele-specific PCR, revealed that it is a variant with an allele frequency of approximatel y 0.5%. Conclusion: P25L is a rare variant of the VHL gene and cannot be considered a cause of VHL disease. However, this work does not prove that P25L is ent irely innocuous.