ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.461C>T (p.Pro154Leu) (rs1399097617)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000804483 SCV000944394 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-10-05 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 154 of the VHL protein (p.Pro154Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families affected with von Hippel-Lindau syndrome (PMID: 20660572, 23143947, 7987306, 25867206, 17024664, 8956040). This variant is also known as c.674C>T (p.Pro225Leu) in the literature. Experimental studies have shown that this missense change affects HIF1 alpha degradation due to a reduced interaction with TBP1 and the proteasome (PMID: 14556007). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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