ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.525C>G (p.Tyr175Ter)

dbSNP: rs5030835
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000549585 SCV000697525 pathogenic Von Hippel-Lindau syndrome 2016-02-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001388392 SCV001589362 pathogenic Chuvash polycythemia; Von Hippel-Lindau syndrome 2020-05-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the VHL gene (p.Tyr175*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acids of the VHL protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the elongin C binding domain (PMID: 14987375), which is required for protein stability and tumor suppressive activity (PMID: 9447969, 10900011). Other variants that disrupt this region (p.Tyr185*) have been determined to be pathogenic (PMID: 23298237, 7987306). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individuals with von Hippel-Lindau (VHL) syndrome (PMID: 9829912, 12202531, 15300849, 27527340). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182974). This variant is not present in population databases (ExAC no frequency).

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