ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.46G>T (p.Glu16Ter) (rs1060503556)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000559942 SCV000626908 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2017-07-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu16*) in the VHL gene. 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 protein translation. 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, 10102622). 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.

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