ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.3G>C (p.Met1Ile)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000707210 SCV000836297 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-05-09 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the VHL mRNA. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with VHL-related disease. 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). Furthermore, knock-in mouse studies investigating the initiator codon find no difference in phenotype or VHL-mediated activities (including degradation of HIFa) compared to wild type (PMID: 23541568). Based on these results, the impact of this variant on VHL protein function is uncertain. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.