ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.188T>A (p.Leu63Gln) (rs104893827)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000767232 SCV000897775 uncertain significance Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV001037923 SCV001201360 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-02-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with glutamine at codon 63 of the VHL protein (p.Leu63Gln). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with bilateral pheochromocytoma (PMID: 19258401, Invitae). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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