ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.486C>G (p.Cys162Trp) (rs5030622)

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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 RCV000567560 SCV000664755 pathogenic Hereditary cancer-predisposing syndrome 2017-09-05 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,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000208792 SCV000264761 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
Invitae RCV000226031 SCV000285499 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 162 of the VHL protein (p.Cys162Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with von Hippel-Lindau disease (PMID: 9829912, 12202531, 19270817, 25867206) and renal cell carcinoma (PMID: 10408776, 15177666). Currently there is insufficient evidence to conclude whether this variant segregates with disease or not. This variant is also known in the literature as c.699C>G (p.Cys233Trp). ClinVar contains an entry for this variant (Variation ID: 223227). One experimental study has shown that this missense change disrupts the VHL-dependent proteasomal degradation failing to induce ubiquination of targeted proteins (PMID: 17350623). This variant disrupts the p.Cys162 amino acid residue in VHL. Other variant that disrupt this residue have been observed in affected individuals (PMID: 11331612), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics RCV000679043 SCV000805353 uncertain significance not provided 2016-10-27 criteria provided, single submitter clinical testing

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