ClinVar

Description

This sequence change falls in intron 1 of the VHL gene. It is not expected to change the encoded amino acid sequence of the VHL protein. However, this sequence change falls within a cryptic exon in the VHL gene, known as exon E1’, which is naturally expressed at low levels in several human tissues (PMID: 29891534). RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal recessive familial erythrocytosis (PMID: 29891534). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 816686). Studies have shown that this variant results in a disruption of the relative levels of naturally occurring VHL mRNA isoforms, increasing expression of exon E1’ containing isoforms and decreasing the expression of the major mRNA isoforms, and introducing a premature termination codon (PMID: 29891534; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.