Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001070434 | SCV001235662 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2020-02-14 | 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. Downstream of the known ATG start site, the nearest methionine codon that can be used to initiate translation of the VHL protein lies at codon 54. Several studies have shown that the VHL protein created from this downstream methionine is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722, 10102622). Based on these results, the impact of this variant on VHL protein function is uncertain. This variant has not been reported in the literature in individuals with VHL-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change results in a premature translational stop signal in the VHL gene p.Ala18Glnfs*49. It is unclear whether it will result in an absent or disrupted protein product because a highly conserved, in-frame methionine located at codon 54 has the potential to rescue this truncating variant. |