ClinVar Miner

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

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000122262 SCV000205377 uncertain significance not specified 2016-12-15 criteria provided, single submitter clinical testing The p.Arg200Trp variant in VHL has not been reported in the heterozygous state i n individuals with paragangliomas, pheochromocytomas, or von Hippel-Lindau syndr ome (Ang 2002, Pastore 2003, Gordeuk 2004, Miasnikova 2011) but is a well establ ished pathogenic variant in the homozygous state for autosomal recessive familia l erythrocytosis, also known as Chuvash polycythemia (Ang 2002, Gordeuk 2004). T his variant has been identified in 10/16278 of South Asian chromosomes by the Ex ome Aggregation Database (ExAc;; dbSNP rs28940298 ). Computational prediction tools and conservation analysis do not provide stron g support for or against an impact to the protein. In summary, the clinical sign ificance of the p.Arg200Trp variant is uncertain as it relates to paragangliomas , pheochromocytomas, and von Hippel-Lindau syndrome.
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 2019-12-18 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 Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Strong segregation with disease (lod >3 = >10 meioses)
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
OMIM RCV000002320 SCV000022478 pathogenic Erythrocytosis, familial, 2 2011-06-19 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000002320 SCV000053268 pathogenic Erythrocytosis, familial, 2 2015-04-03 no assertion criteria provided clinical testing
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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