ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.592C>G (p.Leu198Val)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001323713 SCV001514640 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-01-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 198 of the VHL protein (p.Leu198Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with clinical features of von Hippel-Lindau syndrome (PMID: 18031321). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.198 amino acid residue in VHL. Other variant that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 24555745, 27539324), which suggests that this may be a clinically significant amino acid residue. 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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