ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.292T>C (p.Tyr98His) (rs5030809)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000679029 SCV000203787 pathogenic not provided 2015-03-23 criteria provided, single submitter clinical testing
Invitae RCV000684783 SCV000553393 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 98 of the VHL protein (p.Tyr98His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as a recurrent mutation causing type 2A von Hippel-Lindau (VHL) syndrome in families from the Black Forest region of Germany, and in many other individuals affected with VHL (PMID: 7759077, 7728151, 10408776, 21204227, 19763184, 19336503, 11483638). This variant is associated mostly with pheochromocytoma, hemangioblastoma and retinal hemangioma, with fewer occurrences of renal cell carcinoma (PMID: 11483638). This variant is also known as c.505T>C and p.Tyr169His in the literature. ClinVar contains an entry for this variant (Variation ID: 2223). Experimental studies have shown that this missense changes impairs VHL binding to and ubiquitination of HIF1alpha (PMID: 11331612, 25371412, 10878807, 11331613), and affects protein stability (PMID: 23840444, 16261165) while not completely abolishing ubiquitin ligase activity of the VHL complex in vitro (PMID: 16261165). In addition, cells with this variant have been shown to be defective in microtubule stabilization (PMID: 12510195). Results of these studies are likely relevant to the specific genotype-phenotype effect of this variant. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000492094 SCV000580959 pathogenic Hereditary cancer-predisposing syndrome 2017-02-13 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Well-characterized mutation at same position
Integrated Genetics/Laboratory Corporation of America RCV000002309 SCV000697496 pathogenic Von Hippel-Lindau syndrome 2016-02-11 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679029 SCV000805336 pathogenic not provided 2015-12-24 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000679029 SCV001146628 pathogenic not provided 2019-02-15 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease. However, available data are from a single family.
Johns Hopkins Genomics,Johns Hopkins University RCV000002309 SCV001425361 pathogenic Von Hippel-Lindau syndrome 2020-03-31 criteria provided, single submitter clinical testing
OMIM RCV000002309 SCV000022467 pathogenic Von Hippel-Lindau syndrome 2001-11-01 no assertion criteria provided literature only
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000002309 SCV000264695 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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