ClinVar

Description

Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. This donor splice site variant lies upstream of exon 3 sequence encoding the elongin C binding domain of VHL, which is required for protein stability and tumor suppressive activity (PMID: 9447969, 10900011, 14987375). Variants that disrupt this domain have been determined to be pathogenic (PMID: 9452032, 9829912, 17350623, 19602254, 25371412). This suggests that this region is critical for VHL protein function, and that other variants that disrupt this region may also be pathogenic. This variant has been reported in an individual with a personal and family history of von Hippel-Lindau syndrome (PMID: 8707293). This variant is also known as 676+2C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 569414). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in the last intron (intron 2) of the VHL gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.