ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.491A>G (p.Gln164Arg)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000551.4(VHL):c.491A>G (p.Gln164Arg)
Variation ID: 2238 Accession: VCV000002238.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10149814 (GRCh38) [ NCBI UCSC ] 3: 10191498 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 22, 2016 May 1, 2024 Mar 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.491A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Gln164Arg missense NM_001354723.2:c.*45A>G 3 prime UTR NM_198156.3:c.368A>G NP_937799.1:p.Gln123Arg missense NC_000003.12:g.10149814A>G NC_000003.11:g.10191498A>G NG_008212.3:g.13180A>G NG_046756.1:g.7576A>G LRG_322:g.13180A>G LRG_322t1:c.491A>G LRG_322p1:p.Gln164Arg P40337:p.Gln164Arg - Protein change
- Q164R, Q123R
- Other names
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- Canonical SPDI
- NC_000003.12:10149813:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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VHL | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
832 | 2004 | |
LOC107303340 | - | - | - | GRCh38 | - | 1117 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2021 | RCV000002326.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 26, 2023 | RCV001052383.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 24, 2020 | RCV001023261.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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. |
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Pathogenic
(Jan 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697523.2
First in ClinVar: Aug 22, 2016 Last updated: Feb 12, 2021 |
Comment:
Variant summary: VHL c.491A>G (p.Gln164Arg) results in a conservative amino acid change located in the alpha domain, which is known to interact with Elongin C … (more)
Variant summary: VHL c.491A>G (p.Gln164Arg) results in a conservative amino acid change located in the alpha domain, which is known to interact with Elongin C (IPR024048). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251444 control chromosomes (gnomAD). c.491A>G has been reported in the literature in multiple patients/families affected with Von Hippel-Lindau Syndrome (VHL) or with VHL-related tumors, including at least one individual with de novo occurrence (e.g. Chen_1995, Zbar_1996, Webster_1999, Mattocks_2000, Ong_2007, Sovinz_2010, de Cubas_2013, Neumann_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that while this variant didn't affect elongin B and C binding in an in vitro peptide-binding assay, the Q164R mutant full-length protein had reduced binding ability to elongin B and Cul2 in transiently transfected renal carcinoma cells (Ohh_1999). In addition, another study also reported that though the variant protein had retained elongin C binding, the variant significantly reduced the intracellular stability of VHL protein (Park_2015). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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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
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001216592.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gln164 amino acid residue in VHL. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gln164 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12807974, 19215943, 22517557, 24102379; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 2238). This missense change has been observed in individual(s) with von Hippel-Lindau disease (PMID: 7728151, 17024664, 20583150). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 164 of the VHL protein (p.Gln164Arg). (less)
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Pathogenic
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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von Hippel-Lindau syndrome
Affected status: yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000897835.1
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
Number of individuals with the variant: 3
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Pathogenic
(Sep 24, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001185112.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.Q164R (also known as c.491A>G) pathogenic mutation, located in coding exon 3 of the VHL gene, results from an A to G substitution at … (more)
The p.Q164R (also known as c.491A>G) pathogenic mutation, located in coding exon 3 of the VHL gene, results from an A to G substitution at nucleotide position 491. The glutamine at codon 164 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in patients with clinical diagnoses of von Hippel-Lindau syndrome (VHL), or VHL related tumors (Chen F et al. Hum. Mutat. 1995;5:66-75; Webster AR et al. Arch. Ophthalmol. 1999 Mar;117:371-8; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9; Sovinz P et al. Am. J. Med. Genet. A. 2010 Jul;152A:1752-5; de Cubas AA et al. Endocr. Relat. Cancer. 2013 Aug;20:477-93; Fallon SC et al. J. Pediatr. Surg. 2013 Jun;48:1422-5; Krauss T et al. Endocr. Relat. Cancer. 2018 Sep;25:783-793). In one case, this variant was identified in a 2-year-old child with pheochromocytoma. It was found to be de novo in the patient's father, who also had pheochromocytoma, retinal angioma, and an adrenal adenoma (Sovinz P et al. Am. J. Med. Genet. A. 2010 Jul;152A:1752-5). In vitro functional studies do not show specific impaired functions, including elongin C binding, however, one study showed a shorter protein half-life than wild type leading the authors to speculate that the protein may be unstable (Ohh M et al. J. Clin. Invest. 1999 Dec;104:1583-91; Maynard MA et al. J. Biol. Chem. 2003 Mar;278:11032-40; Park KS et al. BMC Cancer. 2015 Oct;15:800). Another alteration at the same codon, p.Q164H (c.492G>C) , has been reported in a family diagnosed with PGLs and PCCs (Bauters C et al. J. Med. Genet. 2003 Jun;40:e75), and internal structural analysis indicated the alteration disrupts the fold of the elongin binding domain of VHL (Ambry internal data; Van Molle I et al. Chem. Biol. 2012 Oct;19:1300-12). In addition, the p.Q164R variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 01, 2010)
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no assertion criteria provided
Method: literature only
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VON HIPPEL-LINDAU SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022484.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2020 |
Comment on evidence:
In a 2.5-year-old girl who presented with a pheochromocytoma but no other manifestations of von Hippel-Lindau syndrome (VHLS; 193300), Sovinz et al. (2010) identified a … (more)
In a 2.5-year-old girl who presented with a pheochromocytoma but no other manifestations of von Hippel-Lindau syndrome (VHLS; 193300), Sovinz et al. (2010) identified a heterozygous 491A-G transition in exon 3 of the VHL gene, resulting in an gln164-to-arg (Q164R) substitution in a protein surface residue. Genotyping of the family indicated that she inherited the mutation from her father, in whom it occurred de novo. Although he was in good health and asymptomatic, detailed physical examination found a retinal angioma, an adrenal adenoma, and bilateral pheochromocytoma, consistent with VHL syndrome. Sovinz et al. (2010) noted that Ong et al. (2007) had identified the Q164R mutation in a family in which a patient developed pheochromocytoma at age 10 years and retinal angioma at age 23 years, suggesting that this mutation may be associated with early onset of symptoms. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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New Insights Into Pheochromocytoma Surveillance of Young Patients With VHL Missense Mutations. | Fagundes GFC | Journal of the Endocrine Society | 2019 | PMID: 31528828 |
Comparison of Pheochromocytoma-Specific Morbidity and Mortality Among Adults With Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy. | Neumann HPH | JAMA network open | 2019 | PMID: 31397861 |
Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors. | Krauss T | Endocrine-related cancer | 2018 | PMID: 29748190 |
E2-EPF UCP regulates stability and functions of missense mutant pVHL via ubiquitin mediated proteolysis. | Park KS | BMC cancer | 2015 | PMID: 26503325 |
Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas. | McInerney-Leo AM | Clinical endocrinology | 2014 | PMID: 24102379 |
The utility of cortical-sparing adrenalectomy in pheochromocytomas associated with genetic syndromes. | Fallon SC | Journal of pediatric surgery | 2013 | PMID: 23845641 |
Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways. | de Cubas AA | Endocrine-related cancer | 2013 | PMID: 23660872 |
A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma. | Buffet A | Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | 2012 | PMID: 22517557 |
Pheochromocytoma in a 2.75-year-old-girl with a germline von Hippel-Lindau mutation Q164R. | Sovinz P | American journal of medical genetics. Part A | 2010 | PMID: 20583150 |
Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von Hippel-Lindau disease and suggests molecular mechanisms of tumorigenesis. | Forman JR | Proteins | 2009 | PMID: 19408298 |
Denaturing high performance liquid chromatography detection of SDHB, SDHD, and VHL germline mutations in pheochromocytoma. | Meyer-Rochow GY | The Journal of surgical research | 2009 | PMID: 19215943 |
Genotype-phenotype correlations in von Hippel-Lindau disease. | Ong KR | Human mutation | 2007 | PMID: 17024664 |
Hereditary phaeochromocytomas and paragangliomas: a study of five susceptibility genes. | Bauters C | Journal of medical genetics | 2003 | PMID: 12807974 |
Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. | Maynard MA | The Journal of biological chemistry | 2003 | PMID: 12538644 |
Comparative sequence analysis (CSA): a new sequence-based method for the identification and characterization of mutations in DNA. | Mattocks C | Human mutation | 2000 | PMID: 11058902 |
Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. | Ohh M | The Journal of clinical investigation | 1999 | PMID: 10587522 |
Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation. | Webster AR | Archives of ophthalmology (Chicago, Ill. : 1960) | 1999 | PMID: 10088816 |
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 |
Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. | Eng C | Journal of medical genetics | 1995 | PMID: 8825918 |
Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. | Chen F | Human mutation | 1995 | PMID: 7728151 |
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Text-mined citations for rs267607170 ...
HelpRecord last updated Sep 29, 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.