ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.357C>G (p.Phe119Leu) (rs1559428077)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000767262 SCV000897811 pathogenic Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000821822 SCV000962594 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-08-14 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 119 of the VHL protein (p.Phe119Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with von Hippel-Lindau syndrome (PMID: 7728151, 12000816) and in an individual affected with pheochromocytomas (PMID: 19336503). Experimental studies have shown that this missense change impairs protein stability and function (PMID: 23840444, 21715564). A different variant (c.355T>C) giving rise to the same protein effect observed here (p.Phe119Leu) has been reported in an individual affected with von Hippel-Lindau syndrome (PMID: 16142346, 19270817), indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000767262 SCV001737869 pathogenic Von Hippel-Lindau syndrome 2021-06-01 criteria provided, single submitter clinical testing Variant summary: VHL c.357C>G (p.Phe119Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251496 control chromosomes. c.357C>G has been reported in the literature in individuals affected with Von Hippel-Lindau Syndrome (Chen_1995, Zbar_1996, Boedeker_2009, Klein_2001, etc). Experimental studies have shown the variant to impair protein stability, folding and function (Rechsteiner_2011, Shmueli_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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