ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.554A>G (p.Tyr185Cys) (rs561874453)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236099 SCV000293700 uncertain significance not provided 2020-02-25 criteria provided, single submitter clinical testing Observed in an individual with clear cell renal cell carcinoma (Beuselinck 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25583177, 26933808)
Ambry Genetics RCV000565491 SCV000675796 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-31 criteria provided, single submitter clinical testing The p.Y185C variant (also known as c.554A>G), located in coding exon 3 of the VHL gene, results from an A to G substitution at nucleotide position 554. The tyrosine at codon 185 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well 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 RCV000631260 SCV000752288 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 185 of the VHL protein (p.Tyr185Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs561874453, ExAC 0.005%). This variant has been reported in an individual with clear cell renal cell carcinoma (PMID: 25583177). ClinVar contains an entry for this variant (Variation ID: 223232). 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: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Counsyl RCV000208797 SCV000786552 uncertain significance Von Hippel-Lindau syndrome 2018-05-22 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000208797 SCV000264770 uncertain significance Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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