ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.191G>C (p.Arg64Pro) (rs104893826)

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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 RCV000132356 SCV000187445 pathogenic Hereditary cancer-predisposing syndrome 2019-04-17 criteria provided, single submitter clinical testing The p.R64P pathogenic mutation (also known as c.191G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 191. The arginine at codon 64 is replaced by proline, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals and/or families diagnosed with VHL (van der Harst E et al. Int J Cancer. 1998 Jul 29;77(3):337-40; Hoffman MA et al. Hum. Mol. Genet. 2001 May;10:1019-27; Hes FJ et al. Clin Genet. 2007 Aug;72(2):122-9; Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun;94:1938-44; Wittström E et al. Ophthalmic Genet. 2014 Jun;35:91-106). In addition, a 23-year-old female diagnosed with a neck PGL who had a family history of PCCs and clear cell renal cell carcinoma was found to carry this alteration, and her tumor showed LOH for the wild-type allele (Gaal J et al. J Clin Endocrinol Metab. 2009 Nov;94(11):4367-71). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000208872 SCV000264666 pathogenic Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000475973 SCV000553379 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 64 of the VHL protein (p.Arg64Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (rs104893826, ExAC no frequency). This variant has been reported to segregate with Von Hippel-Lindau (VHL) syndrome in several families (PMID: 9663592, 19336503, 17661816), was found as de novo in an individual with pheochromocytoma (PMID: 24555745) and in an unrelated individual with pheochromocytoma (PMID: 17102083). In one family, 2 individuals carrying this variant presented with no typical VHL manifestations after annual clinical monitoring at ages 40 and 59 (PMID: 17661816), suggesting reduced penetrance of this variant. ClinVar contains an entry for this variant (Variation ID: 2226). Experimental studies in vitro show conflicting results concerning the effect this missense change has on the ability of VHL to degrade HIF2 alpha (PMID: 16452184, 11331612, 15611064), but indicate that this variant results in impaired binding to and ubiquitination of HIF1 alpha compared to wild-type VHL (PMID: 15611064, 11331612).  Different studies using different assays also report conflicting results as to whether or not this variant affects the ability of VHL to bind fibronectin and assemble a distinguishable fibronectin matrix (PMID: 11331612, 16452184). However, renal carcinoma cells containing this variant were shown to be capable of inducing relatively late-onset, vascularized and invasive renal cell tumors with aberrant extracellular matrices in a nude mouse xenograft assay, while cells containing wild-type VHL did not induce tumors (PMID: 16452184). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics,PreventionGenetics RCV000679019 SCV000805324 likely pathogenic not provided 2018-02-13 criteria provided, single submitter clinical testing
OMIM RCV000002314 SCV000022472 pathogenic Pheochromocytoma 1998-07-29 no assertion criteria provided literature only

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