ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.525C>G (p.Tyr175Ter) (rs5030835)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000549585 SCV000626876 pathogenic Von Hippel-Lindau syndrome 2017-04-25 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the VHL mRNA at codon 175 (p.Tyr175*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 39 amino acids of the VHL protein. This variant has been reported in a large family affected with von Hippel-Lindau disease (PMID: 9829912, 12202531, 15300849). This truncation deletes the C-terminal portion of the elongin C binding domain (PMID: 14987375), which is required for protein stability and tumor suppressive activity (PMID: 9447969, 10900011). In addition, a missense substitution downstream of this variant (p.Leu188Val) has been determined to be pathogenic (PMID: 7563486, 8772572, 16452184, 18567581). This suggests that the leucine residue at codon 188 is critical for VHL protein function, and that variants that disrupt this position, including this truncating variant, may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
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
Invitae RCV001388392 SCV001589362 pathogenic Erythrocytosis, familial, 2; 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. This variant is not present in population databases (ExAC no frequency). 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 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. For these reasons, this variant has been classified as Pathogenic.

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