ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.524A>T (p.Tyr175Phe) (rs193922613)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001023797 SCV001185718 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing The p.Y175F variant (also known as c.524A>T), located in coding exon 3 of the VHL gene, results from an A to T substitution at nucleotide position 524. The tyrosine at codon 175 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001359453 SCV001555324 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-08-01 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with phenylalanine at codon 175 of the VHL protein (p.Tyr175Phe). The tyrosine residue is moderately conserved and there is a small physicochemical difference between tyrosine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 825586). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Tyr175 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14722919, 30105105, 23859443, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx RCV001536627 SCV001753409 uncertain significance not provided 2020-09-22 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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