ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.5C>T (p.Pro2Leu) (rs111246617)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492422 SCV000580966 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000161089 SCV000211824 uncertain significance not provided 2017-10-18 criteria provided, single submitter clinical testing This variant is denoted VHL c.5C>T at the cDNA level, p.Pro2Leu (P2L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. VHL Pro2Leu was observed at an allele frequency of 0.02% (12/63,398) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether VHL Pro2Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000294881 SCV000439631 uncertain significance Von Hippel-Lindau syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781920 SCV000920339 uncertain significance not specified 2017-10-23 criteria provided, single submitter clinical testing Variant summary: The VHL c.5C>T (p.Pro2Leu) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 12/164682 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000189 (12/63398). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic VHL variant (0.0000208), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as a VUS - possibly benign variant, until additional evidence becomes available.
Invitae RCV000168429 SCV000219126 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 2 of the VHL protein (p.Pro2Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs111246617, ExAC 0.02%). This variant has been observed in an individual undergoing panel testing for hereditary erythrocytosis (PMID: 29790589), and in individuals in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 182981). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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