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
Ambry Genetics RCV000565491 SCV000675796 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Counsyl RCV000208797 SCV000786552 uncertain significance Von Hippel-Lindau syndrome 2018-05-22 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000208797 SCV000264770 uncertain significance Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
GeneDx RCV000236099 SCV000293700 uncertain significance not provided 2017-10-11 criteria provided, single submitter clinical testing This variant is denoted VHL c.554A>G at the cDNA level, p.Tyr185Cys (Y185C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAC>TGC). This variant was identified as a germline variant in a patient with metastatic clear cell renal cell carcinoma (Beuselinck 2015). VHL Tyr185Cys was not observed at a significant frequency in large population cohorts (Lek 2016). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Tyr185Cys occurs at a position that is conserved in mammals and is located within the elongin C binding alpha-domain (Yuen 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether VHL Tyr185Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000631260 SCV000752288 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-11-22 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.

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