ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.563T>G (p.Leu188Arg)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001246640 SCV001420012 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 188 of the VHL protein (p.Leu188Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 21463266). 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. This variant disrupts the p.Leu188 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7563486, 8772572, 7987306, 15642680, 11331612, 16452184, 18567581, 23772956). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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