ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.188T>C (p.Leu63Pro) (rs104893827)

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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 RCV000585971 SCV000697475 uncertain significance not provided 2016-02-04 criteria provided, single submitter clinical testing
Invitae RCV000704785 SCV000833749 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-05-11 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 63 of the VHL protein (p.Leu63Pro). The leucine residue is moderately 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 observed in several individuals affected with pheochromocytoma (PMID: 9663592, 19574279, 17102080). This variant is also known as c.401T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 2227). Experimental studies have shown that this missense change (p.Leu63Pro) produces moderate reduction of Hypoxia-inducible factor 1-alpha (HIF-1a) binding and failed to degrade Hypoxia-inducible factor 2-alpha (HIF-2a). This variant falls in a mutational 'hotspot', which is defined as a clustering of plausible observations within a localized region of the protein. Other missense changes reported in suspected VHL cases include p.Arg64Pro, p.Ser65Trp and p.Ser65Leu, as well as several other missense variants within the same linker region of the protein (PMID: 15611064). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000002315 SCV000022473 pathogenic Pheochromocytoma 1998-07-29 no assertion criteria provided literature only

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