ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.533T>C (p.Leu178Pro) (rs5030822)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492520 SCV000580952 likely pathogenic Hereditary cancer-predisposing syndrome 2017-03-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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,Other strong data supporting pathogenic classification
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000767287 SCV000897845 pathogenic Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000631291 SCV000752319 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2017-09-05 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 178 of the VHL protein (p.Leu178Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with von Hippel-Lindau disease in several families (PMID: 17024664, 19763184).  It has also been reported in several individual affected with von Hippel-Lindau disease (PMID: 27527340, 17024664, 19464396, 19763184). This variant is also known as 746T>C (p.L249P) in the literature. ClinVar contains an entry for this variant (Variation ID: 428795). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

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