This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 200 of the VHL protein (p.Arg200Trp). This variant is present in population databases (rs28940298, gnomAD 0.07%). 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). It has also been observed to segregate with disease in related individuals. This 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%). ClinVar contains an entry for this variant (Variation ID: 2232). 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: 12415268, 15574766, 17992257, 19030229). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.598C>T (p.Arg200Trp)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(21)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Pathogenic(9); Uncertain significance(3); Likely benign(2)
Pathogenic(9); Uncertain significance(3); Likely benign(2)
21
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000551.4(VHL):c.598C>T (p.Arg200Trp)
Variation ID: 2232 Accession: VCV000002232.57
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p25.3 3: 10149921 (GRCh38) [ NCBI UCSC ] 3: 10191605 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 9, 2014 Oct 13, 2024 Sep 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000551.4:c.598C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Arg200Trp missense NM_001354723.2:c.*152C>T 3 prime UTR NM_198156.3:c.475C>T NP_937799.1:p.Arg159Trp missense NC_000003.12:g.10149921C>T NC_000003.11:g.10191605C>T NG_008212.3:g.13287C>T NG_046756.1:g.7683C>T LRG_322:g.13287C>T LRG_322t1:c.598C>T LRG_322p1:p.Arg200Trp P40337:p.Arg200Trp - Protein change
- R200W, R159W
- Other names
-
p.R200W:CGG>TGG
- Canonical SPDI
- NC_000003.12:10149920:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00021
Exome Aggregation Consortium (ExAC) 0.00023
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| VHL | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
832 | 2004 | |
| LOC107303340 | - | - | - | GRCh38 | - | 1117 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Sep 22, 2024 | RCV000002320.15 | |
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Feb 5, 2024 | RCV000148922.12 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Jul 31, 2024 | RCV000122262.15 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Jun 27, 2024 | RCV000161094.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 31, 2022 | RCV000574264.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV000627742.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 20, 2017 | RCV000722031.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 4, 2022 | RCV002247239.4 | |
|
VHL-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 16, 2024 | RCV004742206.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely benign
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
von Hippel-Lindau syndrome
Affected status: yes
Allele origin:
germline
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000897856.1
First in ClinVar: Jul 01, 2016 Last updated: Jul 01, 2016 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Nonpapillary renal cell carcinoma
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002519954.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
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Pathogenic
(Mar 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Chuvash polycythemia
Affected status: yes
Allele origin:
germline
|
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust
Accession: SCV003853410.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
|
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Chuvash polycythemia
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253857.13
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 200 of the VHL protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 200 of the VHL protein (p.Arg200Trp). This variant is present in population databases (rs28940298, gnomAD 0.07%). 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). It has also been observed to segregate with disease in related individuals. This 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%). ClinVar contains an entry for this variant (Variation ID: 2232). 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: 12415268, 15574766, 17992257, 19030229). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Uncertain Significance
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004841671.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces arginine with tryptophan at codon 200 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with tryptophan at codon 200 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). **Functional studies have reported that this variant partially impacted VHL functions to varying degrees in binding and ubiquitination of HIF1alpha and the regulation of genes in the VHL-HIF and VHL-JAK2 pathways (PMID: 12415268, 15574766, 17992257, 19304954, 21685897) and partial to no impact on VHL binding to Elongin B, Elongin C, cullen and ROC/Rbx1 (PMID: 15574766, 19030229). Homozygous and compound heterozygous carriers of this variant have been reported in individuals affected with recessive Chuvash polycythemia and/or erythrocytosis (PMID: 11987242, 12415268, 12393546, 12702509, 12844285, 14726398, 15642664, 16210343, 23403324, 31132167), and haplotype analysis has found that one haplotype with this variant is a founder mutation for recessive Chuvash polycythemia (PMID: 14604959). However, these individuals and heterozygous family members are not known to exhibit multiple CNS and retinal hemangioblastomas and clear cell renal cell carcinomas that are characteristic of VHL hereditary cancer predisposition syndrome. One carrier family that was originally reported to be affected with isolated central nervous system hemangioblastoma (PMID: 17264095) was found to have this variant, p.Arg200Trp, in cis with p.Arg161Gln, and the haplotype of both variants in cis and in heterozygous state segregated with family members affected with CNS and retinal hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma and pancreatic neuroendocrine tumor (PMID: 25371412). Furthermore, functional study found that both variants in cis has an additive deleterious impact on VHL function in HIF1alpha peptide binding and deregulated expression of genes in the VHL-HIF pathway, suggesting the that the haplotype with both variants in cis is associated with autosomal dominant cancer predisposition (PMID: 25371412). This variant is common and has been identified in 57/282754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, the heterozygous state for this variant per se may not be associated with the autosomal dominant VHL hereditary cancer predisposition syndrome. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 44
|
|
|
Uncertain Significance
(Feb 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000205377.7
First in ClinVar: Jan 31, 2015 Last updated: Apr 20, 2024 |
Comment:
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: … (more)
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 (http://gnomad.broadinstitute.org). 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. (less)
|
|
|
Pathogenic
(Jun 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000211829.14
First in ClinVar: Feb 24, 2015 Last updated: Jul 23, 2024 |
Comment:
Published functional studies demonstrate a damaging effect: mice homozygous for variant showed similar phenotype to patients homozygous for the variant (PMID: 17992257); In silico analysis … (more)
Published functional studies demonstrate a damaging effect: mice homozygous for variant showed similar phenotype to patients homozygous for the variant (PMID: 17992257); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; While this variant is considered pathogenic for autosomal recessive Chuvash polycythemia, there is no evidence that it causes increased risk for von Hippel Lindau disease (PMID: 12393546, 12844285, 17264095, 21606165); This variant is associated with the following publications: (PMID: 27568332, 15574766, 25637381, 21876117, 21993671, 27518686, 11987242, 29489754, 33033909, 31132167, 35220195, 19030229, 23015148, 18836774, 24728327, 8956040, 25371412, 12415268, 21606165, 23403324, 9829912, 27651169, 12844285, 12393546, 14726398, 28400504, 28104701, 26556299, 29741264, 29790589, 16210343, 19494350, 31568062, 12702509, 30787465, 35142155, 34308104, 35767051, 17264095, 17992257, 38390862, 37317877, 37553354, 37833987, 36744932, 37946251) (less)
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Uncertain significance
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760273.4
First in ClinVar: Dec 17, 2022 Last updated: Aug 04, 2024 |
|
|
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Pathogenic
(Sep 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Chuvash polycythemia
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005373931.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
|
|
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Pathogenic
(Jan 20, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Acute leukemia of ambiguous lineage
Affected status: yes
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV000853208.1
First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018 |
Comment:
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 … (more)
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. (less)
Sex: male
|
|
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Pathogenic
(Nov 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Erythrocytosis, familial, 2
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053268.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 07, 2020 |
Comment:
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 … (more)
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). (less)
|
|
|
Pathogenic
(Feb 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449948.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
|
|
|
Likely benign
(Aug 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000488867.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000664473.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Feb 26, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Chuvash polycythemia
Affected status: unknown
Allele origin:
germline
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000264776.1
First in ClinVar: Mar 08, 2016 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 9
|
|
|
Pathogenic
(Jun 19, 2011)
|
no assertion criteria provided
Method: literature only
|
POLYCYTHEMIA, CHUVASH TYPE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022478.6
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
Chuvash polycythemia (see ECYT2, 263400), caused by this specific arg200-to-trp (R200W) mutation in the VHL gene, is an autosomal recessive disorder of erythrocytosis that is … (more)
Chuvash polycythemia (see ECYT2, 263400), caused by this specific arg200-to-trp (R200W) mutation in the VHL gene, is an autosomal recessive disorder of erythrocytosis that is endemic to the mid-Volga River region. Ang et al. (2002) studied 5 multiplex Chuvash families and confirmed that polycythemia was associated with significant elevations of serum erythropoietin (EPO; 133170) levels and ruled out a location of the gene on chromosome 11 as had been reported previously by Vasserman et al. (1999). They also ruled out mutation in the HIF1A gene (603348), which is located in 14q. Using a genomewide screen, they identified a region on 3p with a lod score greater than 2 and identified a 598C-T transition in the VHL gene, resulting in an arg200-to-trp (R200W) mutation in all cases. Ang et al. (2002) concluded that the R200W substitution impairs the interaction of VHL with HIF1-alpha, reducing the rate of degradation of HIF1-alpha and resulting in increased expression of downstream target genes including EPO, SLC2A1 (138140), transferrin (TF; 190000), transferrin receptor (TFRC; 190010), and vascular endothelial growth factor (VEGF; 192240). Mutations in VHL had been associated with pheochromocytoma, hemangioblastoma, and renal cell carcinoma, none of which were observed in individuals with Chuvash polycythemia or obligate carriers of the R200W mutation. Ang et al. (2002) stated that more than 700 mutations had been reported in VHL (Beroud et al., 1998), but that no individual had been found to be homozygous or compound heterozygous for germline mutations. Pastore et al. (2003) evaluated the role of the VHL gene in 8 children with a history of polycythemia and an elevated serum EPO level and identified 3 different germline VHL mutations in 4 of them. One child was homozygous for the R200W mutation, and another was compound heterozygous for the R200W mutation and a val130-to-leu mutation (V130L; 608537.0021). Of 2 sibs who were heterozygous for an asp126-to-tyr mutation (D126Y; 608537.0022), 1 fulfilled some criteria of VHL syndrome (193300); a pulmonary angioma was discovered at 10 years of age and treated by coil embolization without effect on the polycythemia, and at 15 years of age nephrectomy was performed for a subcapsular hemangioma. Percy et al. (2002) observed homozygosity for the R200W mutation in 3 Bangladeshi families with Chuvash-type congenital polycythemia living in the United Kingdom. By haplotype analysis of 101 ethnically diverse individuals with the common R200W mutation, including 72 Chuvash individuals, Liu et al. (2004) determined that the R200W mutation is due to a founder effect that originated from 14,000 to 62,000 years ago. In a matched cohort study, Gordeuk et al. (2004) found that homozygosity for the 598C-T transition in the VHL gene was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum VEGF concentrations (p less than 0.0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classic VHL syndrome were not found, suggesting that overexpression of HIF1-alpha and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in 598C-T homozygotes than in controls, erythropoietin response to hypoxia was identical. Gordeuk et al. (2004) concluded that Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes. Cario et al. (2005) reported a Turkish patient who was homozygous for the R200W mutation. Haplotype analysis showed a different haplotype than that associated with the Chuvash population, indicating that the mutation arose independently and is not geographically restricted. Perrotta et al. (2006) found that the R200W missense mutation (598C-T) causing Chuvash polycythemia is more frequent on the island of Ischia in the Bay of Naples (0.070) than it is in Chuvashia (0.057). The haplotype of all patients in Ischia matched that identified in the Chuvash cluster, thus supporting the single founder hypothesis. Perrotta et al. (2006) also found that unaffected heterozygotes had increased HIF1-alpha activity, which might confer a biochemical advantage for mutation maintenance. They suggested that this form of familial polycythemia may be endemic in other regions of the world, a hypothesis supported by the reports of Percy et al. (2002, 2003). Russell et al. (2011) presented evidence suggesting 2 main molecular mechanisms by which the R200W and H191D (608537.0024) VHL mutations result in polycythemia. In vitro studies showed that the R200W mutation attenuated formation of the E3 ubiquitin ligase and attenuated binding of HIF1 (603348). In patients, this would lead to overproduction of the HIF-target erythropoietin (EPO; 133170) and thus secondary polycythemia. In addition, VHL mutations result in conformational changes causing increased binding to SOCS1 (603597), which inhibits binding and degradation of phosphorylated JAK2 (147796). The resulting pJAK2 stabilization promotes hyperactivation of the JAK2-STAT5 (601511) pathway in erythroid progenitors, causing hypersensitivity to erythropoietin and thereby to primary polycythemia. Treatment of R200W/R200W transgenic mice with a JAK2 inhibitor resulted in decreased hematocrit, smaller spleen, and decreased sensitivity to EPO compared to untreated transgenic mice. Tomasic et al. (2013) stated that Russell et al. (2011) erroneously quoted the H191D mutation as a Chuvash polycythemia variant. The data presented by Tomasic et al. (2013) showed that erythrocyte precursors from homozygous H191D patients did not exhibit intrinsic hyperproliferation or a hyperproliferative response to EPO, as observed in R200W homozygotes. Their studies indicated different functional effects of the mutations. (less)
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Pathogenic
(Sep 16, 2024)
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no assertion criteria provided
Method: clinical testing
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VHL-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005349982.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The VHL c.598C>T variant is predicted to result in the amino acid substitution p.Arg200Trp. While pathogenic variants in the VHL gene are typically associated with … (more)
The VHL c.598C>T variant is predicted to result in the amino acid substitution p.Arg200Trp. While pathogenic variants in the VHL gene are typically associated with autosomal dominant von Hippel-Lindau (VHL) disease, this variant has been reported to be a common causative variant for autosomal recessive familial erythrocytosis type 2, also known as Chuvash polycythemia (Sergeyeva et al. 1997. PubMed ID: 9058738; Ang et al. 2002. PubMed ID: 11987242; Semenza et al. 2009. PubMed ID: 19494350). This variant has been reported in the gnomAD public population database in a global subpopulation up to 0.065%, but is present in the Chuvash population of Russia at an allele frequency of 5.7% and on the island of Ischia in Italy at an allele frequency of 7% (Perrotta et al. 2005. PubMed ID: 16210343). Mice homozygous for this variant exhibited polycythemia, but no increase in tumors associated with VHL disease were observed (Hickey et al. 2007. PubMed ID: 17992257). This variant has not been reported to cause VHL disease in humans (Gordeuk et al. 2004. PubMed ID: 14726398; Pastore et al. 2003. PubMed ID: 12844285; Miasnikova et al. 2011. PubMed ID: 21606165), although some evidence suggests it may be causative with a low penetrance (Woodward et al. 2007. PubMed ID: 17264095). We classify this variant as pathogenic, in the context of autosomal recessive Chuvash polycythemia. For autosomal dominant VHL syndrome, although we suspect it may be benign, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Likely benign
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Von Hippel-Lindau syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190679.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Likely pathogenic
(Apr 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Chuvash polycythemia
Affected status: yes
Allele origin:
germline
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Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927919.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000086487.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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not provided
(-)
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no classification provided
Method: phenotyping only
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Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002074976.1
First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022 |
Comment:
Variant interpreted as Pathogenic and reported on 10-29-2020 by Lab or GTR ID 507401. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 10-29-2020 by Lab or GTR ID 507401. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Goiter (present) , Hyperthyroidism (present) , Hypermetropia (present) , Tinnitus (present) , Anxiety (present) , Depression (present) , Cafe au lait spots, multiple (present) , … (more)
Goiter (present) , Hyperthyroidism (present) , Hypermetropia (present) , Tinnitus (present) , Anxiety (present) , Depression (present) , Cafe au lait spots, multiple (present) , Cutis laxa (present) , Abnormal esophagus morphology (present) , Abnormal erythrocyte morphology (present) , Thyroid tumor (present) (less)
Indication for testing: Diagnostic
Age: 40-49 years
Sex: female
Testing laboratory: BioReference Laboratories
Date variant was reported to submitter: 2020-10-29
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
This missense variant replaces arginine with tryptophan at codon 200 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). **Functional studies have reported that this variant partially impacted VHL functions to varying degrees in binding and ubiquitination of HIF1alpha and the regulation of genes in the VHL-HIF and VHL-JAK2 pathways (PMID: 12415268, 15574766, 17992257, 19304954, 21685897) and partial to no impact on VHL binding to Elongin B, Elongin C, cullen and ROC/Rbx1 (PMID: 15574766, 19030229). Homozygous and compound heterozygous carriers of this variant have been reported in individuals affected with recessive Chuvash polycythemia and/or erythrocytosis (PMID: 11987242, 12415268, 12393546, 12702509, 12844285, 14726398, 15642664, 16210343, 23403324, 31132167), and haplotype analysis has found that one haplotype with this variant is a founder mutation for recessive Chuvash polycythemia (PMID: 14604959). However, these individuals and heterozygous family members are not known to exhibit multiple CNS and retinal hemangioblastomas and clear cell renal cell carcinomas that are characteristic of VHL hereditary cancer predisposition syndrome. One carrier family that was originally reported to be affected with isolated central nervous system hemangioblastoma (PMID: 17264095) was found to have this variant, p.Arg200Trp, in cis with p.Arg161Gln, and the haplotype of both variants in cis and in heterozygous state segregated with family members affected with CNS and retinal hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma and pancreatic neuroendocrine tumor (PMID: 25371412). Furthermore, functional study found that both variants in cis has an additive deleterious impact on VHL function in HIF1alpha peptide binding and deregulated expression of genes in the VHL-HIF pathway, suggesting the that the haplotype with both variants in cis is associated with autosomal dominant cancer predisposition (PMID: 25371412). This variant is common and has been identified in 57/282754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, the heterozygous state for this variant per se may not be associated with the autosomal dominant VHL hereditary cancer predisposition syndrome. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
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 (http://gnomad.broadinstitute.org). 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.
Comment:
Published functional studies demonstrate a damaging effect: mice homozygous for variant showed similar phenotype to patients homozygous for the variant (PMID: 17992257); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; While this variant is considered pathogenic for autosomal recessive Chuvash polycythemia, there is no evidence that it causes increased risk for von Hippel Lindau disease (PMID: 12393546, 12844285, 17264095, 21606165); This variant is associated with the following publications: (PMID: 27568332, 15574766, 25637381, 21876117, 21993671, 27518686, 11987242, 29489754, 33033909, 31132167, 35220195, 19030229, 23015148, 18836774, 24728327, 8956040, 25371412, 12415268, 21606165, 23403324, 9829912, 27651169, 12844285, 12393546, 14726398, 28400504, 28104701, 26556299, 29741264, 29790589, 16210343, 19494350, 31568062, 12702509, 30787465, 35142155, 34308104, 35767051, 17264095, 17992257, 38390862, 37317877, 37553354, 37833987, 36744932, 37946251)
Comment:
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.
Comment:
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).
Comment:
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.
Comment:
The VHL c.598C>T variant is predicted to result in the amino acid substitution p.Arg200Trp. While pathogenic variants in the VHL gene are typically associated with autosomal dominant von Hippel-Lindau (VHL) disease, this variant has been reported to be a common causative variant for autosomal recessive familial erythrocytosis type 2, also known as Chuvash polycythemia (Sergeyeva et al. 1997. PubMed ID: 9058738; Ang et al. 2002. PubMed ID: 11987242; Semenza et al. 2009. PubMed ID: 19494350). This variant has been reported in the gnomAD public population database in a global subpopulation up to 0.065%, but is present in the Chuvash population of Russia at an allele frequency of 5.7% and on the island of Ischia in Italy at an allele frequency of 7% (Perrotta et al. 2005. PubMed ID: 16210343). Mice homozygous for this variant exhibited polycythemia, but no increase in tumors associated with VHL disease were observed (Hickey et al. 2007. PubMed ID: 17992257). This variant has not been reported to cause VHL disease in humans (Gordeuk et al. 2004. PubMed ID: 14726398; Pastore et al. 2003. PubMed ID: 12844285; Miasnikova et al. 2011. PubMed ID: 21606165), although some evidence suggests it may be causative with a low penetrance (Woodward et al. 2007. PubMed ID: 17264095). We classify this variant as pathogenic, in the context of autosomal recessive Chuvash polycythemia. For autosomal dominant VHL syndrome, although we suspect it may be benign, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Comment:
Variant interpreted as Pathogenic and reported on 10-29-2020 by Lab or GTR ID 507401. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 200 of the VHL protein (p.Arg200Trp). This variant is present in population databases (rs28940298, gnomAD 0.07%). 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). It has also been observed to segregate with disease in related individuals. This 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%). ClinVar contains an entry for this variant (Variation ID: 2232). 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: 12415268, 15574766, 17992257, 19030229). For these reasons, this variant has been classified as Pathogenic.
Comment:
This missense variant replaces arginine with tryptophan at codon 200 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). **Functional studies have reported that this variant partially impacted VHL functions to varying degrees in binding and ubiquitination of HIF1alpha and the regulation of genes in the VHL-HIF and VHL-JAK2 pathways (PMID: 12415268, 15574766, 17992257, 19304954, 21685897) and partial to no impact on VHL binding to Elongin B, Elongin C, cullen and ROC/Rbx1 (PMID: 15574766, 19030229). Homozygous and compound heterozygous carriers of this variant have been reported in individuals affected with recessive Chuvash polycythemia and/or erythrocytosis (PMID: 11987242, 12415268, 12393546, 12702509, 12844285, 14726398, 15642664, 16210343, 23403324, 31132167), and haplotype analysis has found that one haplotype with this variant is a founder mutation for recessive Chuvash polycythemia (PMID: 14604959). However, these individuals and heterozygous family members are not known to exhibit multiple CNS and retinal hemangioblastomas and clear cell renal cell carcinomas that are characteristic of VHL hereditary cancer predisposition syndrome. One carrier family that was originally reported to be affected with isolated central nervous system hemangioblastoma (PMID: 17264095) was found to have this variant, p.Arg200Trp, in cis with p.Arg161Gln, and the haplotype of both variants in cis and in heterozygous state segregated with family members affected with CNS and retinal hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma and pancreatic neuroendocrine tumor (PMID: 25371412). Furthermore, functional study found that both variants in cis has an additive deleterious impact on VHL function in HIF1alpha peptide binding and deregulated expression of genes in the VHL-HIF pathway, suggesting the that the haplotype with both variants in cis is associated with autosomal dominant cancer predisposition (PMID: 25371412). This variant is common and has been identified in 57/282754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, the heterozygous state for this variant per se may not be associated with the autosomal dominant VHL hereditary cancer predisposition syndrome. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
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 (http://gnomad.broadinstitute.org). 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.
Comment:
Published functional studies demonstrate a damaging effect: mice homozygous for variant showed similar phenotype to patients homozygous for the variant (PMID: 17992257); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; While this variant is considered pathogenic for autosomal recessive Chuvash polycythemia, there is no evidence that it causes increased risk for von Hippel Lindau disease (PMID: 12393546, 12844285, 17264095, 21606165); This variant is associated with the following publications: (PMID: 27568332, 15574766, 25637381, 21876117, 21993671, 27518686, 11987242, 29489754, 33033909, 31132167, 35220195, 19030229, 23015148, 18836774, 24728327, 8956040, 25371412, 12415268, 21606165, 23403324, 9829912, 27651169, 12844285, 12393546, 14726398, 28400504, 28104701, 26556299, 29741264, 29790589, 16210343, 19494350, 31568062, 12702509, 30787465, 35142155, 34308104, 35767051, 17264095, 17992257, 38390862, 37317877, 37553354, 37833987, 36744932, 37946251)
Comment:
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.
Comment:
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).
Comment:
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.
Comment:
The VHL c.598C>T variant is predicted to result in the amino acid substitution p.Arg200Trp. While pathogenic variants in the VHL gene are typically associated with autosomal dominant von Hippel-Lindau (VHL) disease, this variant has been reported to be a common causative variant for autosomal recessive familial erythrocytosis type 2, also known as Chuvash polycythemia (Sergeyeva et al. 1997. PubMed ID: 9058738; Ang et al. 2002. PubMed ID: 11987242; Semenza et al. 2009. PubMed ID: 19494350). This variant has been reported in the gnomAD public population database in a global subpopulation up to 0.065%, but is present in the Chuvash population of Russia at an allele frequency of 5.7% and on the island of Ischia in Italy at an allele frequency of 7% (Perrotta et al. 2005. PubMed ID: 16210343). Mice homozygous for this variant exhibited polycythemia, but no increase in tumors associated with VHL disease were observed (Hickey et al. 2007. PubMed ID: 17992257). This variant has not been reported to cause VHL disease in humans (Gordeuk et al. 2004. PubMed ID: 14726398; Pastore et al. 2003. PubMed ID: 12844285; Miasnikova et al. 2011. PubMed ID: 21606165), although some evidence suggests it may be causative with a low penetrance (Woodward et al. 2007. PubMed ID: 17264095). We classify this variant as pathogenic, in the context of autosomal recessive Chuvash polycythemia. For autosomal dominant VHL syndrome, although we suspect it may be benign, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Comment:
Variant interpreted as Pathogenic and reported on 10-29-2020 by Lab or GTR ID 507401. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic basis of unexplained erythrocytosis in Indian patients. | Mallik N | European journal of haematology | 2019 | PMID: 31132167 |
| Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
| Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis. | Couvé S | Cancer research | 2014 | PMID: 25371412 |
| Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
| The phenotype of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C>T:R200W). | Tomasic NL | Haematologica | 2013 | PMID: 23403324 |
| Decreased serum glucose and glycosylated hemoglobin levels in patients with Chuvash polycythemia: a role for HIF in glucose metabolism. | McClain DA | Journal of molecular medicine (Berlin, Germany) | 2013 | PMID: 23015148 |
| Von hippel-lindau disease and erythrocytosis. | Capodimonti S | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22393103 |
| Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHL(R200W) mutation (Chuvash polycythemia). | Sable CA | Haematologica | 2012 | PMID: 21993671 |
| Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression. | Gordeuk VR | Blood | 2011 | PMID: 21876117 |
| Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia. | Russell RC | Nature medicine | 2011 | PMID: 21685897 |
| The heterozygote advantage of the Chuvash polycythemia VHLR200W mutation may be protection against anemia. | Miasnikova GY | Haematologica | 2011 | PMID: 21606165 |
| Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. | Semenza GL | Blood | 2009 | PMID: 19494350 |
| Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia. | van Rooijen E | Blood | 2009 | PMID: 19304954 |
| VHL type 2B mutations retain VBC complex form and function. | Hacker KE | PloS one | 2008 | PMID: 19030229 |
| Computational detection of deleterious SNPs and their effect on sequence and structural level of the VHL gene. | Rajasekaran R | Mammalian genome : official journal of the International Mammalian Genome Society | 2008 | PMID: 18836774 |
| von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. | Hickey MM | The Journal of clinical investigation | 2007 | PMID: 17992257 |
| VHL mutation analysis in patients with isolated central nervous system haemangioblastoma. | Woodward ER | Brain : a journal of neurology | 2007 | PMID: 17264095 |
| Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster. | Perrotta S | Blood | 2006 | PMID: 16210343 |
| Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHL-haplotype analysis in patients with presumable congenital erythrocytosis. | Cario H | Haematologica | 2005 | PMID: 15642664 |
| In vitro and in vivo models analyzing von Hippel-Lindau disease-specific mutations. | Rathmell WK | Cancer research | 2004 | PMID: 15574766 |
| Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. | Gordeuk VR | Blood | 2004 | PMID: 14726398 |
| The worldwide distribution of the VHL 598C>T mutation indicates a single founding event. | Liu E | Blood | 2004 | PMID: 14604959 |
| Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. | Pastore Y | American journal of human genetics | 2003 | PMID: 12844285 |
| Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry. | Percy MJ | Blood | 2003 | PMID: 12702509 |
| Mutations in the VHL gene in sporadic apparently congenital polycythemia. | Pastore YD | Blood | 2003 | PMID: 12393546 |
| Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. | Ang SO | Nature genetics | 2002 | PMID: 12415268 |
| Endemic polycythemia in Russia: mutation in the VHL gene. | Ang SO | Blood cells, molecules & diseases | 2002 | PMID: 11987242 |
| Localization of the gene responsible for familial benign polycythemia to chromosome 11q23. | Vasserman NN | Human heredity | 1999 | PMID: 10364675 |
| Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. | Olschwang S | Human mutation | 1998 | PMID: 9829912 |
| Software and database for the analysis of mutations in the VHL gene. | Béroud C | Nucleic acids research | 1998 | PMID: 9399847 |
| Congenital polycythemia in Chuvashia. | Sergeyeva A | Blood | 1997 | PMID: 9058738 |
| Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. | Zbar B | Human mutation | 1996 | PMID: 8956040 |
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Text-mined citations for rs28940298 ...
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Record last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.