3-10149921-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PM5PP3PP5BS1_Supporting
The NM_000551.4(VHL):c.598C>T(p.Arg200Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R200Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000551.4 missense
Scores
Clinical Significance
Conservation
Publications
- pheochromocytomaInheritance: AD Classification: DEFINITIVE Submitted by: G2P
- von Hippel-Lindau diseaseInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
- renal cell carcinomaInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- autosomal recessive secondary polycythemia not associated with VHL geneInheritance: AR Classification: STRONG Submitted by: Ambry Genetics
- Chuvash polycythemiaInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| VHL | NM_000551.4 | c.598C>T | p.Arg200Trp | missense_variant | Exon 3 of 3 | ENST00000256474.3 | NP_000542.1 | |
| VHL | NM_198156.3 | c.475C>T | p.Arg159Trp | missense_variant | Exon 2 of 2 | NP_937799.1 | ||
| VHL | NR_176335.1 | n.927C>T | non_coding_transcript_exon_variant | Exon 4 of 4 | ||||
| VHL | NM_001354723.2 | c.*152C>T | 3_prime_UTR_variant | Exon 3 of 3 | NP_001341652.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| VHL | ENST00000256474.3 | c.598C>T | p.Arg200Trp | missense_variant | Exon 3 of 3 | 1 | NM_000551.4 | ENSP00000256474.3 |
Frequencies
GnomAD3 genomes 0.0000854 AC: 13AN: 152176Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000211 AC: 53AN: 251358 AF XY: 0.000294 show subpopulations
GnomAD4 exome AF: 0.000240 AC: 351AN: 1461844Hom.: 1 Cov.: 30 AF XY: 0.000271 AC XY: 197AN XY: 727224 show subpopulations
Age Distribution
GnomAD4 genome 0.0000854 AC: 13AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74326 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Chuvash polycythemia Pathogenic:6
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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). -
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Von Hippel-Lindau syndrome Uncertain:2Benign:3Other:1
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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. -
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. -
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. -
not provided Pathogenic:3Uncertain:2
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, 32191290, 30787465, 35142155, 34308104, 35767051, 17264095, 17992257, 38390862, 37317877, 37553354, 37833987, 36744932, 37946251, 37372416, 38201513) -
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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. -
The VHL c.598C>T (p.Arg200Trp) variant has been reported to cause the autosomal recessive disorder known as Chuvash polycythemia, however, most studies indicate that this variant is not associated with an increased risk for classic von Hippel-Lindau syndrome associated tumors (PMIDs: 12415268 (2002), 14726398 (2004), and 21606165 (2011)). Functional evidence suggests that this variant (known in the literature as R200W) may impact protein function and impair the hypoxia response pathway thus providing an underlying mechanistic basis for Chuvash polycythemia in homozygous individuals (PMIDs: 12415268 (2002), 17992257 (2007), and 19030229 (2008)). The frequency of this variant in the general population, 0.00065 (20/30604 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
The VHL c.598C>T; p.Arg200Trp variant (rs28940298) is an established founder mutation associated with autosomal recessive familial erythrocytosis 2 (MIM 263400), congenital polycythemia, or Chuvash polycythemia in a homozygous state (Ang 2002a, Ang 2002b, Pastore 2003, Percy 2003, Perrotta 2006). This variant is also reported in ClinVar (Variation ID: 2232). It is found in the general population with an overall allele frequency of 0.02% (57/282754 alleles, including zero homozygotes), and in the South Asian population with an allele frequency of 0.07% (20/30604 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.867). Several studies have demonstrated experimentally that this variant alters the function of the VHL protein (Ang 2002b, Hickey 2007, Rathmell 2004). Based on available information, this variant is considered to be pathogenic. References: Ang SO et al. Endemic polycythemia in Russia: mutation in the VHL gene. Blood Cells Mol Dis. 2002a Jan-Feb. PMID: 11987242. Ang SO et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nature genetics. 2002b Dec. PMID: 12415268. Hickey MM et al. von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. J Clin Invest. 2007 Dec. PMID: 17992257. Pastore YD et al. Mutations in the VHL gene in sporadic apparently congenital polycythemia. Blood. 2003 Feb 15. PMID: 12393546. Percy MJ et al. Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry. Blood. 2003 Aug 1. PMID: 12702509. Perrotta S et al. Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster. Blood. 2006 Jan 15. PMID: 16210343. Rathmell WK et al. In vitro and in vivo models analyzing von Hippel-Lindau disease-specific mutations. Cancer Res. 2004 Dec 1. PMID: 15574766. -
not specified Uncertain:1Other:1
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VHL-related disorder Pathogenic:1
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. -
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
Nonpapillary renal cell carcinoma Pathogenic:1
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Hereditary cancer-predisposing syndrome Pathogenic:1
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. -
Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1
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Acute leukemia of ambiguous lineage Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at