Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Center for Genomic Medicine, |
RCV002465984 | SCV002760266 | uncertain significance | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV004007469 | SCV004841629 | uncertain significance | Von Hippel-Lindau syndrome | 2023-06-28 | criteria provided, single submitter | clinical testing | 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, VHL encodes a smaller protein isoform from internal translation initiation at methionine 54 (PMID: 9671762, 10102622). Functional studies have reported that the smaller protein isoform can rescue VHL functions in renal carcinoma cells lacking endogenous VHL expression (PMID: 9671762, 9751722, 10102622) and a mouse model for VHL start codon loss found that most VHL functions are intact (PMID: 23541568). This nonsense mutation, c.34G>T (p.Glu12*) is not expected to disrupt the expression of the smaller functional isoform. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31378 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. |