ClinVar

Description

This variant changes 1 nucleotide in exon 1 of the VHL gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. However, there is a naturally occurring VHL protein isoform that has start of translation at methionine 54 and appears to retain tumor suppressor activity (PMID: 9671762, 9751722, 10102622), which may ameliorate the deleterious effects of this N-terminal frameshift. To our knowledge, functional studies have not been reported for this variant. This variant has been reported three individuals affected with VHL-associated clinical features including one individual affected with central nervous system hemangioblastoma and pancreatic cyst (PMID: 21463266), an individual affected with multiple retinal and cerebellar hemangioblastoma (PMID: 34566400), and an individual affected with renal cell carcinoma (PMID: 28873162). This variant also has been reported in one individual each affected with pancreatic and breast cancer (PMID: 26681312, 28454591), two individuals affected with erythrocytosis (PMID: 27651169, 29790589) and an individual affected with malignant pleural mesothelioma (PMID: 35032816). This variant has been identified in 4/222880 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of VHL function is a known mechanism of disease (clinicalgenome.org). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.