ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.524A>G (p.Tyr175Cys) (rs193922613)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030589 SCV000053266 likely pathogenic Von Hippel-Lindau syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Ambry Genetics RCV000492408 SCV000580980 pathogenic Hereditary cancer-predisposing syndrome 2020-10-09 criteria provided, single submitter clinical testing The p.Y175C pathogenic mutation(also known as c.524A>G), located in coding exon 3 of the VHL gene, results from an A to G substitution at nucleotide position 524. The tyrosine at codon 175 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this alteration was described in a patient with a personal and family history of pheochromocytoma, and was reported to segregate with disease in this family (Ruiz-Llorente S et al. Hum. Mutat. 2004;23(2):160-9). This alteration has been identified in several patients with VHL-related tumors (de Cubas AA et al. Endocr. Relat. Cancer 2013 Aug; 20(4):477-93; Ambry internal data). One publication suggests that the p.Y175C alteration may be considered "borderline," with a loss of function insufficient to induce renal cancer but still capable to cause pheochromocytoma (Couvé S et al. Cancer Res. 2014 Nov; 74(22):6554-64). Further, a similar alteration at the same location, p.Y175N (c.523T>A), has been described in an individual with multiple hemangioblastomas and bilateral pheochromocytoma (Ruiz-Llorente S et al. Hum. Mutat. 2004;23(2):160-9). Of note, some literature suggests the p.Y175C alteration may be associated with erythrocytosis. In one such study, this alteration was seen in a Portuguese female diagnosed with erythrocytosis at age 17. However, the alteration was found to be inherited from the father, who was reported to have normal hematological parameters; this patient also had a diagnosis of ataxia–telangiectasia (Bento C et al. Eur. J. Haematol. 2013 Oct; 91(4):361-8). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Van Molle I et al. Chem. Biol., 2012 Oct;19:1300-12; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000533687 SCV000626909 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-12-07 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 175 of the VHL protein (p.Tyr175Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with von Hippel-Lindau (VHL) syndrome in two families (PMID: 14722919, Invitae). This variant has also been observed in individuals with a personal and/or family history of VHL-associated tumors (PMID: 30105105, Invitae), and an individual affected with erythrocytosis (PMID: 23859443). ClinVar contains an entry for this variant (Variation ID: 36905). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C2). A different missense substitution at this codon (p.Tyr175Asn) has been reported in an individual affected with von Hippel-Lindau (VHL) syndrome (PMID: 14722919). For these reasons, this variant has been classified as Pathogenic.

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.