ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.524A>G (p.Tyr175Cys) (rs193922613)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America 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 likely pathogenic Hereditary cancer-predisposing syndrome 2016-06-03 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,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Well-characterized mutation at same position,Other data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000533687 SCV000626909 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-11-17 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 175 of the VHL protein (p.Tyr175Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with von Hippel-Lindau (VHL) syndrome in two families (PMID: 14722919, Invitae). This variant has also been observed in individuals with personal and/or family history of VHL-associated tumors (PMID: 30105105, Invitae) and an individual affected with erythrocytosis (PMID: 23859443). ClinVar contains an entry for this variant (Variation ID: 36905). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C25"). A different missense substitution at this codon (p.Tyr175Asn) has been reported in an individual affected with von Hippel-Lindau (VHL) syndrome (PMID: 14722919). For these reasons, this variant has been classified as Pathogenic.

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