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 2018-12-24 criteria provided, single submitter clinical testing This variant is denoted c.473 T>C at the cDNA level or p.Leu158Pro (L158P) at the protein level. The L158P missense pathogenic variant in the VHL gene has been reported previously in association with von Hippel-Lindau syndrome (VHL) using alternate nomenclature (Whaley et al., 1994). Studies of the L158P mutant in a VHL-null renal cell line (RCC10) have shown that this variant affects the function of VHL protein (Bangiyeva et al., 2009). The variant is found in VHL panel(s).
Ambry Genetics RCV000492547 SCV000580975 pathogenic Hereditary cancer-predisposing syndrome 2014-12-19 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Other strong data supporting pathogenic classification;Well-characterized mutation at same position
Integrated Genetics/Laboratory Corporation of America 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 2019-06-05 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.
Division of Genomic Diagnostics,The 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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