ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.598C>T (p.Arg200Trp) (rs28940298)

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Total submissions: 13
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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 RCV000002320 SCV000053268 pathogenic Erythrocytosis, familial, 2 2020-11-23 criteria provided, single submitter clinical testing Variant summary: VHL c.598C>T (p.Arg200Trp) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, alpha domain (IPR024048) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251358 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in VHL causing Congenital Polycythemia (0.00021 vs 0.02), allowing no conclusion about variant significance. c.598C>T has been reported in the literature, primarily in the homozygous state, in multiple individuals affected with autosomal recessive Congenital Polycythemia, also referred to as familial erythrocytosis type 2 (Chuvash polycythemia) (e.g. Ang_2002, Pastore_2003, Percy_2003, Perrotta_2006). These data indicate that the variant is very likely to be associated with Congenital Polycythemia. In the heterozygous state, the variant is not expected to cause Von Hippel-Lindau Syndrome, as reported by multiple studies (e.g. Ang_2002, Pastore_2003, Gordeuk_2004, Miasnikova_2011). Experimental evidence demonstrated the variant reduced the affinity of VHL for HIF1-alpha, resulting in a reduced rate of ubiquitination under non-hypoxic conditions (Ang_2002). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Additionally, two ClinVar submitters (evaluation after 2014) cite it as likely benign for the condition of von Hippel-Lindau syndrome. Based on the evidence outlined above, the variant was classified as pathogenic for Congenital Polycythemia (familial erythrocytosis type 2).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000122262 SCV000205377 uncertain significance not specified 2020-08-10 criteria provided, single submitter clinical testing The p.Arg200Trp variant in VHL has not been reported in the heterozygous state in individuals with paragangliomas, pheochromocytomas, or von Hippel-Lindau syndrome (Ang 2002 PMID: 12415268, Pastore 2003 PMID: 12393546, Gordeuk 2004 PMID: 14726398, Miasnikova 2011 PMID: 21606165) or in individuals with haemangioblastoma (Woodward 2007 PMID: 17264095). However, it is a well-established pathogenic variant in the homozygous state for autosomal recessive familial erythrocytosis, also known as Chuvash polycythemia (Ang 2002 PMID: 12415268, Gordeuk 2004 PMID: 14726398, Perrota 2006 PMID: 16210343, Mallik 2019 PMID: 31132167). It has also been identified in 0.065% (20/30604) of South Asian chromosomes by gnomAD ( This variant has also been reported in ClinVar (Variation ID 2232). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg200Trp variant is uncertain as it relates to paragangliomas, pheochromocytomas, and von Hippel-Lindau syndrome. ACMG/AMP Criteria applied: PM2_Supporting.
GeneDx RCV000161094 SCV000211829 pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing This variant is denoted VHL c.598C>T at the cDNA level, p.Arg200Trp (R200W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). VHL Arg200Trp was observed at an allele frequency of 0.02% (58/277,164) in large population cohorts (Lek 2016). This variant is located within the Beta domain (Yuen 2009). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. VHL Arg200Trp has been reported in the homozygous state to cause Chuvash polycythemia, a disorder characterized by thrombosis, vascular abnormalities, and elevated levels of hypoxia inducible factors (Gordeuk 2004, Hickey 2007, Maher 2011, Sergueeva 2017). Importantly, heterozygous VHL Arg200Trp carriers have not been found to be at an increased risk for classic von Hippel-Lindau syndrome-associated tumors (Pastore 2003, Woodward 2007, Miasnikova 2011). We therefore consider this variant to be pathogenic in regards to Chuvash polycythemia; however, it is unlikely to increase the risk for von Hippel-Lindau-associated tumors.
Invitae RCV000627742 SCV000253857 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 200 of the VHL protein (p.Arg200Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This pathogenic variant is a known common cause of autosomal recessive, familial erythrocytosis type 2 (Chuvash polycythemia) in the Chuvash population of Russia and the Italian island of Ischia (PMID: 11987242, 19494350, 9058738, 16210343). In the Chuvash population, an estimated 1/20 individuals is a carrier of this variant (PMID: 12415268), while the worldwide carrier frequency is lower (rs28940298, 0.06%). This variant has been observed in a family affected with von Hippel-Lindau syndrome without pheochromocytoma (PMID: 8956040), however, several studies have reported that this variant does not cause von Hippel-Lindau syndrome (PMID: 14726398, 21606165). ClinVar contains an entry for this variant (Variation ID: 2232). Experimental studies have shown that this missense change disrupts the normal regulation of the hypoxia response pathway (PMID: 15574766, 19030229, 12415268). Mice homozygous for the Arg200Trp missense change develop polycythemia, mimicking the human disease. Of note, these mice were not predisposed to develop tumors (PMID: 17992257). For these reasons, this variant has been classified as Pathogenic for familial erythrocytosis, type 2. However, this missense change is not likely to confer risk for von Hippel-Lindau syndrome.
Counsyl RCV000148922 SCV000488867 likely benign Von Hippel-Lindau syndrome 2016-08-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000574264 SCV000664473 pathogenic Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing The p.R200W pathogenic mutation (also known as c.598C>T), located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 598. The arginine at codon 200 is replaced by tryptophan, an amino acid with dissimilar properties. The p.R200W alteration has been established as a founder mutation known to cause autosomal recessive Chuvash polycythemia, a condition characterized by increased red blood cell mass and high risk of peripheral thrombosis and cerebrovascular events (Ang SO et al. Nat. Genet. 2002 Dec;32:614-21; Liu E et al. Blood. 2004 Mar;103:1937-40; Gordeuk VR et al. Blood. 2004 May;103:3924-32; Tomasic NL et al. Haematologica. 2013 Apr;98(4):560-7). Functional studies on this alteration have yielded varying results on different aspects of VHL function linked to tumor formation or erythropoeisis, such as increased angiogenesis and increased hypoxia-inducible factor (HIF1a and HIF2a) expression, but retention of interaction with Elongin C (Ang SO et al. Nat. Genet. 2002 Dec;32:614-21; Rathmell WK et al. Cancer Res. 2004 Dec;64:8595-603; Hickey MM et al. J. Clin. Invest. 2007 Dec;117:3879-89; Hacker KE et al. PLoS ONE. 2008 Nov;3:e3801; Gordeuk VR et al. Blood. 2011 Nov;118:5278-82; Couvé S et al. Cancer Res. 2014 Nov;74:6554-64). Although two unrelated individuals with isolated hemangioblastoma have been reported as p.R200W heterozygotes, the vast majority of carriers are not affected with von Hippel Lindau (VHL) lesions (Pastore Y et al. Am. J. Hum. Genet. 2003 Aug;73:412-9; Woodward ER et al. Brain. 2007 Mar;130(Pt 3):836-42). In addition, one family with a clinical diagnosis of VHL was initially reported as being heterozygous for p.R200W (Olschwang S et al. Hum. Mutat. 1998;12:424-30); however, further studies of this family found that they actually carried two VHL alterations in cis (p.R200W and p.R161Q) (Couvé S et al. Cancer Res. 2014 Nov;74:6554-64). By evaluating structural stability in areas of domain interaction, pVHL-HIF1a binding ability, and expression gradients of genes regulated by VHL, the authors were able to demonstrate that the impact of the double mutant allele was more disruptive to structural and functional roles of VHL than the impact of either alteration alone. They proposed that the p.R200W alteration was not sufficient in causing classic VHL disease. This ​ amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, p.R200W is interpreted as a disease-causing mutation. At this time, individuals who are heterozygous for the p.R200W alteration can be interpreted as carriers for Chuvash polycythemia; however, it is unlikely that this alteration causes von Hippel Lindau disease.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000722031 SCV000853208 pathogenic Acute leukemia of ambiguous lineage 2017-01-20 criteria provided, single submitter clinical testing This is a missense alteration in which a C is replaced by a T at coding nucleotide 598 and is predicted to change an Arginine to a Tryptophan at amino acid codon 200. Classification criteria: PS1 (associated with Chuvash syndrome, only in homozygous state), PS3, PM2, PP3.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000148922 SCV000897856 likely benign Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000161094 SCV001449948 pathogenic not provided 2019-02-14 criteria provided, single submitter clinical testing
OMIM RCV000002320 SCV000022478 pathogenic Erythrocytosis, familial, 2 2011-06-19 no assertion criteria provided literature only
ITMI RCV000122262 SCV000086487 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148922 SCV000190679 likely benign Von Hippel-Lindau syndrome 2014-06-01 no assertion criteria provided research
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000002320 SCV000264776 pathogenic Erythrocytosis, familial, 2 2016-02-26 no assertion criteria provided clinical testing

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