ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.242C>T (p.Pro81Leu) (rs193922608)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030582 SCV000053258 likely pathogenic Von Hippel-Lindau syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Ambry Genetics RCV000129974 SCV000184798 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing The p.P81L variant (also known as c.242C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 242. The proline at codon 81 is replaced by leucine, an amino acid with very few similar properties.<span style="background-color:initial"> <span style="background-color:initial">This alteration has been observed in an individual with a right carotid body PGL (Piccini V et al. Endocr Relat Cancer. 2012 Apr 10;19(2):149-55), a patient with a left para-adrenal PGL (Castellano M et al. Ann N Y Acad Sci. 2006 Aug;1073:156-65), and in an individual diagnosed with VHL type 2C (Formenti F et al. FASEB J. 2011 Jun;25(6):2001-11). Based on the limited clinical data presented in the literature, it appears individuals with this alteration do not present with classic VHL, but possibly with VHL type 2C. This amino acid position is highly conserved through mammals, but is not conserved in lower vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001034657 SCV000553390 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-01-23 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 81 of the VHL protein (p.Pro81Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs193922608, ExAC 0.007%). This variant has been reported in individuals with pheochromocytoma (PMID: 21389259, 27730413, 24134185, Invitae) and paraganglioma (PMID: 22241717, 17102082, Invitae). ClinVar contains an entry for this variant (Variation ID: 36899). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV001547784 SCV001767572 likely pathogenic not provided 2020-03-23 criteria provided, single submitter clinical testing Observed in individuals with isolated pheochromocytoma and/or paraganglioma and no other features of von Hippel Lindau syndrome (Castellano 2006, Piccini 2012, Kim 2014, ClinVar SCV000553390.2); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as c.455C>T, p.Pro152Leu, and p.Pro122Leu; This variant is associated with the following publications: (PMID: 21389259, 24134185, 17102082, 22241717, 29946849, 24446253, 27730413)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000030582 SCV000264681 likely pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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