ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.264G>T (p.Trp88Cys) (rs869025622)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492552 SCV000580958 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000208827 SCV000264688 likely pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
Invitae RCV000537014 SCV000626890 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2017-12-18 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 88 of the VHL protein (p.Trp88Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in at least two individuals with a clinical diagnosis of von Hippel-Lindau (VHL) disease (PMID: 10567493, Invitae). ClinVar contains an entry for this variant (Variation ID: 223171). An experimental study has shown that this missense change causes destabilization of hypoxia inducible factor alpha (HIFa) (PMID: 21715564). Two different missense substitutions at this codon (p.Trp88Arg and p.Trp88Ser) have been reported in individuals and families affected with VHL (PMID: 12624160, 7728151, 8634692). This suggests that the tryptophan residue is critical for VHL protein function and that other missense substitutions at this position may also be damaging. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000208827 SCV000967005 likely pathogenic Von Hippel-Lindau syndrome 2018-03-27 criteria provided, single submitter clinical testing The p.Trp88Cys variant in VHL has been reported in at least 5 individuals with v on Hippel-Landau syndrome (VHL; Glasker 1999, Clinvar Variation ID: 223171), and was absent from large population studies. In vitro functional studies provide s ome evidence that the p.Trp88Cys variant may impact protein function (Reschestei ner 2011). Computational prediction tools and conservation analysis suggest that the p.Trp88Cys variant may impact the protein. Additionally, other missense va riants at this position (p.Trp88Arg and p.Trp88Ser) have been reported in indivi duals with VHL (Glasker 2001, Rocha 2003, Chen 1995, Ong 2007, Jilg 2012, Stanoj evic 2007, Wong 2016), suggesting that a change at this amino acid position is n ot tolerated. In summary, although additional studies are required to fully esta blish its clinical significance, the p.Trp88Cys variant is likely pathogenic. AC MG/AMP criteria applied (Richards 2015): PM2; PM5; PP3; PS3_supporting; PS4_supp orting.

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