Submissions for variant NM_000551.4(VHL):c.524A>G (p.Tyr175Cys)

dbSNP: rs193922613

Total submissions: 4

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	2024-04-19	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533687	SCV000626909	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 175 of the VHL protein (p.Tyr175Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with a personal and/or family history of VHL-associated tumors, erythrocytosis and von Hippel-Lindau (VHL) syndrome (PMID: 14722919, 23859443, 30105105; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36905). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. This variant disrupts the p.Tyr175 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 14722919), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV004700288	SCV005202017	likely pathogenic	not provided	2023-10-11	criteria provided, single submitter	clinical testing	Variant was paternally inherited in an individual with congenital polycythemia and ataxia-telangiectasia in published literature, in which a second pathogenic variant was not detected (Bento et al., 2005); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23660872, 18538455, 30105105, 25371412, 17640059, 16969113, 16210343, 31149315, 24115288, 15642681, 17454194, 28620007, 23859443, 24969085, 34566400, 14722919, 34439168, 15642680, 30943211)