Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000208872 | SCV005187306 | pathogenic | Von Hippel-Lindau syndrome | 2024-06-25 | reviewed by expert panel | curation | The NM_000551.3(VHL):c.191G>C (p.Arg64Pro) variant in the VHL gene is absent from gnomAD v4.1.0 (PM2_Supporting). This variant resides within a region, amino acids 63 - 155 (Beta domain), of VHL that is defined as a mutational hotspot and critical functional domain by the ClinGen VHL VCEP (PM1). The computational predictor REVEL gives a score of 0.938, which is above the threshold of 0.664, evidence that correlates with impact to VHL function (PP3). This variant has been reported in 11 probands with features of Von-Hippel-Lindau syndrome/ meeting Danish criteria (9.25 points, PS4; PMID: 19336503, 9663592, 17661816, 30455982, 28646318, 31383958, 19576851, 17639058, 28944243, 17102083, 21463266). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in an individual with bilateral pheochromocytoma (PM6_Supporting; PMID: 24555745). In vitro assays show conflicting results but suggest this variant impacts protein function as shown by reduced binding and ubiquitination of HIF-alpha (PMID: 16452184, 15611064, 11331612) (PS3_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). |
Ambry Genetics | RCV000132356 | SCV000187445 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-11-26 | 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Genomic Diagnostic Laboratory, |
RCV000208872 | SCV000264666 | pathogenic | Von Hippel-Lindau syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000475973 | SCV000553379 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2024-01-05 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 64 of the VHL protein (p.Arg64Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Von Hippel-Lindau (VHL) syndrome and pheochromocytoma (PMID: 9663592, 17102083, 17661816, 19336503, 24555745). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2226). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects VHL function (PMID: 11331612, 15611064, 16452184). For these reasons, this variant has been classified as Pathogenic. |
Prevention |
RCV000679019 | SCV000805324 | likely pathogenic | not provided | 2018-02-13 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000679019 | SCV004034858 | pathogenic | not provided | 2024-03-25 | criteria provided, single submitter | clinical testing | While some published functional studies support a damaging effect including reduced hypoxia-inducible factor (HIF)-1a binding, inability to degrade HIF2a, impaired EPO receptor (EPOR) binding, and defective fibronectin extracellular matrix (ECM) assembly, others demonstrate retained HIF1a binding, retained ability to degrade HIF2a, normal downregulation of HIFa target genes, and retained VEC complex formation (PMID: 11331612, 12944410, 15611064, 16452184, 17700531, 26846855); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.404G>A, p.(R105P); This variant is associated with the following publications: (PMID: 19408298, 18836774, 29748190, 21463266, 19336503, 9663592, 19808854, 17661816, 19576851, 17639058, 17102083, 20151405, 18043261, 26269449, 30877234, 28944243, 28646318, 11331612, 16452184, 15611064, 17700531, 12944410, 26846855, 24555745, 19955664, 32832168, 32487141) |
OMIM | RCV000002314 | SCV000022472 | pathogenic | Pheochromocytoma | 1998-07-29 | no assertion criteria provided | literature only |