ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.473T>C (p.Leu158Pro) (rs121913346)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161088 SCV000211823 pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: reduced HIF1-alpha ubiquinitation, disrupted stability, impaired ability to bind to elongin B and C, and disrupted folding of the VHL protein (Feldman 1999, Kamura 2000, McClellan 2005, Bangiyeva 2009); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 686T>C, Leu229Pro; This variant is associated with the following publications: (PMID: 8956040, 10635329, 11331612, 7977367, 6582782, 12202531, 15300849, 17661816, 9829912, 10973499, 15935760, 14987375, 27535533, 19955664, 19602254)
Ambry Genetics RCV000492547 SCV000580975 pathogenic Hereditary cancer-predisposing syndrome 2020-03-28 criteria provided, single submitter clinical testing The p.L158P pathogenic mutation (also known as c.473T>C), located in coding exon 3 of the VHL gene, results from a T to C substitution at nucleotide position 473. The leucine at codon 158 is replaced by proline, an amino acid with similar properties. This variant has been reported in several families with VHL (Whaley JM et al. Am. J. Hum. Genet. 1994 Dec;55(6):1092-102; Olschwang S et al. Hum Mutat. 1998;12(6):424-30; Ambry internal data). Of note, this variant may be referred to as c.686T>C in older literature.This alteration has been shown to disrupt the ability of the chaperone complex elongin-BC to bind to the VHL protein which leads to improper protein folding (McClellan AJ et al. Cell. 2005 Jun 3;121(5):739-48). One in vitro functional study showed that this variant produced an unstable VHL protein. The authors also show that a p.L158P mutant cell line displayed the same disorganized, fibroblastic morphology as seen in other VHL mutants, and classified this variant as a type 1 VHL mutation (Bangiyeva V et al.. BMC Cancer. 2009 Jul 14;9:229). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000208846 SCV000697519 pathogenic Von Hippel-Lindau syndrome 2016-02-04 criteria provided, single submitter clinical testing Variant summary: The c.473T>C variant affects a conserved nucleotide, resulting in amino acid change from Leu to Pro. 4/4 in-silico tools predict damaging outcome for this variant. This variant has been reported in at least 8 VHL patients and not found in 120292 control chromosomes. In addition, one clinical laboratory classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Invitae RCV001072084 SCV001237427 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-03-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 158 of the VHL protein (p.Leu158Pro). The leucine residue is highly 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 individuals affected with von Hippel-Lindau syndrome and sporadic renal cell carcinoma (PMID: 20351605, 7728151, 7977367, 15300849, 25867206, 23070752, 12202531, 17661816, 10408776, 1056348, Invitae). This variant is also known as 686T>C (Leu229Pro) in the literature. ClinVar contains an entry for this variant (Variation ID: 182980). This variant has been reported to affect VHL protein function (PMID:28775317, 7553625, 11331613, 19602254). This variant disrupts the p.Leu158 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19574279, 10761708, 14722919, 28052007). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000208846 SCV000264754 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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