Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000631282 | SCV000752310 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2022-12-04 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Several studies have shown that the VHL protein created from a downstream methionine located at codon 54 is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722). ClinVar contains an entry for this variant (Variation ID: 526683). This variant has not been reported in the literature in individuals affected with VHL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val20Serfs*47) in the VHL gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 54 has the potential to rescue this variant. |
| Ambry Genetics | RCV003302987 | SCV004006358 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-21 | criteria provided, single submitter | clinical testing | The c.57delC variant, located in coding exon 1 of the VHL gene, results from a deletion of one nucleotide at nucleotide position 57, causing a translational frameshift with a predicted alternate stop codon (p.V20Sfs*47). Premature stop codons are typically deleterious in nature; however, an alternate initiation codon exists twenty-four residues downstream of this alteration, and is reported to result in a biologically active isoform, known as VHL19 (Schoenfeld A et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Jul; 95(15):8817-22; Iliopoulos O et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Sep; 95(20):11661-6). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| All of Us Research Program, |
RCV004002811 | SCV004822386 | uncertain significance | Von Hippel-Lindau syndrome | 2023-04-03 | criteria provided, single submitter | clinical testing | This variant deletes 1 nucleotide in exon 1 of the VHL gene, creating a frameshift and premature translation stop signal. 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, this variant has not been reported in individuals affected with VHL-related disorders in the literature. This variant has not been identified 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. |