The VHL c.481C>T; p.Arg161Ter variant (rs5030818), also known as c.694C>T for traditional nomenclature, is reported multiple times in the literature in association with von Hippel-Lindau disease (see Cybulski 2002, Glavac 1996, Nordstrom-O'Brien 2010, Stolle 1998, Zbar 1996). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 2217), and it is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-medicated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Cybulski C et al. Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. J Med Genet. 2002 Jul;39(7):E38. Glavac D et al. Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe. Hum Genet. 1996 Sep;98(3):271-80. Nordstrom-O'Brien M et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010 May;31(5):521-37. Stolle C et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat. 1998;12(6):417-23. Zbar B et al. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996;8(4):348-57.
ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.481C>T (p.Arg161Ter)
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.
(13)
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.
Pathogenic
13
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000551.4(VHL):c.481C>T (p.Arg161Ter)
Variation ID: 2217 Accession: VCV000002217.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p25.3 3: 10149804 (GRCh38) [ NCBI UCSC ] 3: 10191488 (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 Apr 4, 2013 May 1, 2024 Dec 29, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000551.4:c.481C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Arg161Ter nonsense NM_001354723.2:c.*35C>T 3 prime UTR NM_198156.3:c.358C>T NP_937799.1:p.Arg120Ter nonsense NC_000003.12:g.10149804C>T NC_000003.11:g.10191488C>T NG_008212.3:g.13170C>T NG_046756.1:g.7566C>T LRG_322:g.13170C>T LRG_322t1:c.481C>T LRG_322p1:p.Arg161Ter - Protein change
- R161*, R120*
- Other names
-
p.R161*:CGA>TGA
- Canonical SPDI
- NC_000003.12:10149803: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) 0.00000
- 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 (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 22, 2019 | RCV000002301.21 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 7, 2023 | RCV000161091.26 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000437445.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 17, 2023 | RCV000492225.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 29, 2023 | RCV000791367.14 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 27, 2017 | RCV001280922.8 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884875.1
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
Comment:
The VHL c.481C>T; p.Arg161Ter variant (rs5030818), also known as c.694C>T for traditional nomenclature, is reported multiple times in the literature in association with von Hippel-Lindau … (more)
The VHL c.481C>T; p.Arg161Ter variant (rs5030818), also known as c.694C>T for traditional nomenclature, is reported multiple times in the literature in association with von Hippel-Lindau disease (see Cybulski 2002, Glavac 1996, Nordstrom-O'Brien 2010, Stolle 1998, Zbar 1996). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 2217), and it is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-medicated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Cybulski C et al. Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. J Med Genet. 2002 Jul;39(7):E38. Glavac D et al. Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe. Hum Genet. 1996 Sep;98(3):271-80. Nordstrom-O'Brien M et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010 May;31(5):521-37. Stolle C et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat. 1998;12(6):417-23. Zbar B et al. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996;8(4):348-57. (less)
|
|
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Pathogenic
(Dec 29, 2023)
|
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: SCV000553380.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg161*) in the VHL gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg161*) in the VHL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the VHL protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 7987306, 8956040, 9452032, 9829911, 9829912, 10567493, 12114495, 14722919, 15300849, 18446368, 19270817, 21362373, 24206762, 24301059, 25867206). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.694C>T. ClinVar contains an entry for this variant (Variation ID: 2217). This variant disrupts the p.Arg161 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 9829911, 12000816, 14767570, 15300849, 20120764, 21362373, 23842656, 24707167). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 28, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000228904.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
|
Pathogenic
(Jul 22, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053265.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 22, 2020 |
Comment:
Variant summary: VHL c.481C>T (p.Arg161X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: VHL c.481C>T (p.Arg161X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251440 control chromosomes. c.481C>T has been extensively reported in the literature spanning over two decades to co-segregate with disease among multiple affected individuals from families with Von Hippel-Lindau Syndrome (example, Loeb_1994, Zbar_1996, Maher_1996, Li_1998, Cybulski_2002, Ruiz-Llorente_2004, Gallou_2004). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained during this review. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(May 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
|
Clinical Genomics Labs, University Health Network
Accession: SCV001950138.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(Feb 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000211826.13
First in ClinVar: Feb 24, 2015 Last updated: Feb 18, 2023 |
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 53 amino acids are lost, and other loss-of-function variants have been … (more)
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 53 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21362373, 26514359, 23070752, 9829911, 12114495, 10408776, 21972040, 8956040, 25867206, 27527340, 7987306, 25720320, 24581539, 18446368, 9829912, 19574279, 11409863, 19996202, 28630796, 14987375, 9681856, 17661816, 11309459, 20064270, 16572651, 28849724, 7987327, 28469506, 30787465, 33720516, 20233476, 32782288, 32974018) (less)
|
|
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Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011309.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Pathogenic
(Apr 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000580965.7
First in ClinVar: Jul 01, 2017 Last updated: May 01, 2024 |
Comment:
The p.R161* pathogenic mutation (also known as c.481C>T) located in coding exon 3 of the VHL gene, results from a C to T substitution at … (more)
The p.R161* pathogenic mutation (also known as c.481C>T) located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 481. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been reported in several individuals with personal and family histories of Von Hippel-Lindau (VHL) syndrome (Cho HJ et al. J Korean Med Sci. 2009 Feb;24:77-83; Siu WK et al. Chin. Med. J. 2011 Jan;124:237-41; Zbar B et al. Hum. Mutat. 1996;8:348-57; Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; Wong M et al. Chin J Cancer. 2016 Aug;35:79; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). A 48 year old male with bilateral renal clear cell carcinoma and a clinical diagnosis of VHL was found to be a mosaic carrier of this pathogenic mutation (Coppin L et al. Eur. J. Hum. Genet. 2014 Sept;22:1149-52). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
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Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Renal cell carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000505322.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Oct 16, 2007)
|
no assertion criteria provided
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060202.5
First in ClinVar: May 03, 2013 Last updated: Aug 14, 2019 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Dec 01, 1995)
|
no assertion criteria provided
Method: literature only
|
VON HIPPEL-LINDAU SYNDROME
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000022459.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 09, 2020 |
Comment on evidence:
Following the revised codon numbering system of Kuzmin et al. (1995), the ARG232TER mutation has been renumbered as ARG161TER (R161X). In a patient with von … (more)
Following the revised codon numbering system of Kuzmin et al. (1995), the ARG232TER mutation has been renumbered as ARG161TER (R161X). In a patient with von Hippel-Lindau syndrome (VHLS; 193300), Loeb et al. (1994) identified a 694C-T transition in exon 3 of the VHL gene, resulting in an amber stop codon arg232-to-ter (R232X). Gilcrease et al. (1995) found the identical 694C-T transition as a somatic mutation in a clear cell papillary cystadenoma of the epididymis in a patient who showed no evidence of von Hippel-Lindau syndrome and in whom somatic cells did not contain this mutation. (less)
|
|
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Pathogenic
(Dec 27, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Familial infantile myasthenia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
tested-inconclusive
|
Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences
Accession: SCV001450647.1
First in ClinVar: Jan 09, 2021 Last updated: Jan 09, 2021 |
Number of individuals with the variant: 1
Age: 30-39 years
Sex: male
Ethnicity/Population group: Iranian
Geographic origin: Iran
Comment on evidence:
A 31-year-old man with bilateral ptosis, limited eye movement, moderate proximal muscle weakness, and facial weakness since childhood.
|
|
|
Pathogenic
(Feb 26, 2016)
|
no assertion criteria provided
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: SCV000264756.1
First in ClinVar: Mar 08, 2016 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 32
|
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Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg161*) in the VHL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the VHL protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 7987306, 8956040, 9452032, 9829911, 9829912, 10567493, 12114495, 14722919, 15300849, 18446368, 19270817, 21362373, 24206762, 24301059, 25867206). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.694C>T. ClinVar contains an entry for this variant (Variation ID: 2217). This variant disrupts the p.Arg161 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 9829911, 12000816, 14767570, 15300849, 20120764, 21362373, 23842656, 24707167). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: VHL c.481C>T (p.Arg161X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251440 control chromosomes. c.481C>T has been extensively reported in the literature spanning over two decades to co-segregate with disease among multiple affected individuals from families with Von Hippel-Lindau Syndrome (example, Loeb_1994, Zbar_1996, Maher_1996, Li_1998, Cybulski_2002, Ruiz-Llorente_2004, Gallou_2004). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained during this review. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 53 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21362373, 26514359, 23070752, 9829911, 12114495, 10408776, 21972040, 8956040, 25867206, 27527340, 7987306, 25720320, 24581539, 18446368, 9829912, 19574279, 11409863, 19996202, 28630796, 14987375, 9681856, 17661816, 11309459, 20064270, 16572651, 28849724, 7987327, 28469506, 30787465, 33720516, 20233476, 32782288, 32974018)
Comment:
The p.R161* pathogenic mutation (also known as c.481C>T) located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 481. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been reported in several individuals with personal and family histories of Von Hippel-Lindau (VHL) syndrome (Cho HJ et al. J Korean Med Sci. 2009 Feb;24:77-83; Siu WK et al. Chin. Med. J. 2011 Jan;124:237-41; Zbar B et al. Hum. Mutat. 1996;8:348-57; Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; Wong M et al. Chin J Cancer. 2016 Aug;35:79; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). A 48 year old male with bilateral renal clear cell carcinoma and a clinical diagnosis of VHL was found to be a mosaic carrier of this pathogenic mutation (Coppin L et al. Eur. J. Hum. Genet. 2014 Sept;22:1149-52). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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:
The VHL c.481C>T; p.Arg161Ter variant (rs5030818), also known as c.694C>T for traditional nomenclature, is reported multiple times in the literature in association with von Hippel-Lindau disease (see Cybulski 2002, Glavac 1996, Nordstrom-O'Brien 2010, Stolle 1998, Zbar 1996). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 2217), and it is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-medicated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Cybulski C et al. Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. J Med Genet. 2002 Jul;39(7):E38. Glavac D et al. Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe. Hum Genet. 1996 Sep;98(3):271-80. Nordstrom-O'Brien M et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010 May;31(5):521-37. Stolle C et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat. 1998;12(6):417-23. Zbar B et al. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996;8(4):348-57.
Comment:
This sequence change creates a premature translational stop signal (p.Arg161*) in the VHL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the VHL protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 7987306, 8956040, 9452032, 9829911, 9829912, 10567493, 12114495, 14722919, 15300849, 18446368, 19270817, 21362373, 24206762, 24301059, 25867206). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.694C>T. ClinVar contains an entry for this variant (Variation ID: 2217). This variant disrupts the p.Arg161 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 9829911, 12000816, 14767570, 15300849, 20120764, 21362373, 23842656, 24707167). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: VHL c.481C>T (p.Arg161X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251440 control chromosomes. c.481C>T has been extensively reported in the literature spanning over two decades to co-segregate with disease among multiple affected individuals from families with Von Hippel-Lindau Syndrome (example, Loeb_1994, Zbar_1996, Maher_1996, Li_1998, Cybulski_2002, Ruiz-Llorente_2004, Gallou_2004). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained during this review. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 53 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21362373, 26514359, 23070752, 9829911, 12114495, 10408776, 21972040, 8956040, 25867206, 27527340, 7987306, 25720320, 24581539, 18446368, 9829912, 19574279, 11409863, 19996202, 28630796, 14987375, 9681856, 17661816, 11309459, 20064270, 16572651, 28849724, 7987327, 28469506, 30787465, 33720516, 20233476, 32782288, 32974018)
Comment:
The p.R161* pathogenic mutation (also known as c.481C>T) located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 481. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been reported in several individuals with personal and family histories of Von Hippel-Lindau (VHL) syndrome (Cho HJ et al. J Korean Med Sci. 2009 Feb;24:77-83; Siu WK et al. Chin. Med. J. 2011 Jan;124:237-41; Zbar B et al. Hum. Mutat. 1996;8:348-57; Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; Wong M et al. Chin J Cancer. 2016 Aug;35:79; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). A 48 year old male with bilateral renal clear cell carcinoma and a clinical diagnosis of VHL was found to be a mosaic carrier of this pathogenic mutation (Coppin L et al. Eur. J. Hum. Genet. 2014 Sept;22:1149-52). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| VHL Germline Mutations in Argentinian Patients with Clinical Diagnoses or Single Typical Manifestations of Type 1 von Hippel-Lindau Disease. | Mathó C | Genetic testing and molecular biomarkers | 2016 | PMID: 27617348 |
| Clinical and molecular characteristics of East Asian patients with von Hippel-Lindau syndrome. | Wong M | Chinese journal of cancer | 2016 | PMID: 27527340 |
| Characterization of endolymphatic sac tumors and von Hippel-Lindau disease in the International Endolymphatic Sac Tumor Registry. | Bausch B | Head & neck | 2016 | PMID: 25867206 |
| SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T). | Papathomas TG | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2015 | PMID: 25720320 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Bilateral papillopathy as a presenting sign of pheochromocytoma associated with von Hippel-Lindau disease. | Shah V | Clinical ophthalmology (Auckland, N.Z.) | 2014 | PMID: 24707167 |
| VHL mosaicism can be detected by clinical next-generation sequencing and is not restricted to patients with a mild phenotype. | Coppin L | European journal of human genetics : EJHG | 2014 | PMID: 24301059 |
| Persistent exudative retinal detachment after photodynamic therapy and intravitreal bevacizumab injection for multiple retinal capillary hemangiomas in a patient with von Hippel-Lindau disease. | Tsai FY | Journal of the Chinese Medical Association : JCMA | 2014 | PMID: 24206762 |
| p.N78S and p.R161Q germline mutations of the VHL gene are present in von Hippel-Lindau syndrome in two pedigrees. | Qi XP | Molecular medicine reports | 2013 | PMID: 23842656 |
| Molecular basis of von Hippel-Lindau syndrome in Chinese patients. | Siu WK | Chinese medical journal | 2011 | PMID: 21362373 |
| Bilateral pheochromocytoma as first presentation of von Hippel-Lindau disease in a Chinese family. | Tong AL | Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih | 2009 | PMID: 20120764 |
| Improved detection of germline mutations in Korean VHL patients by multiple ligation-dependent probe amplification analysis. | Cho HJ | Journal of Korean medical science | 2009 | PMID: 19270817 |
| Germline mutations in the von Hippel-Lindau disease (VHL) gene in mainland Chinese families. | Zhang J | Journal of cancer research and clinical oncology | 2008 | PMID: 18446368 |
| Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions. | Gallou C | Human mutation | 2004 | PMID: 15300849 |
| A variety of phenotype with R161Q germline mutation of the von Hippel-Lindau tumor suppressor gene in Japanese kindred. | Iida K | International journal of molecular medicine | 2004 | PMID: 14767570 |
| Genetic characterization and structural analysis of VHL Spanish families to define genotype-phenotype correlations. | Ruiz-Llorente S | Human mutation | 2004 | PMID: 14722919 |
| Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. | Cybulski C | Journal of medical genetics | 2002 | PMID: 12114495 |
| Germ-line mutations in nonsyndromic pheochromocytoma. | Neumann HP | The New England journal of medicine | 2002 | PMID: 12000816 |
| The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system. | Gläsker S | Journal of neurology, neurosurgery, and psychiatry | 1999 | PMID: 10567493 |
| Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. | Olschwang S | Human mutation | 1998 | PMID: 9829912 |
| Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. | Stolle C | Human mutation | 1998 | PMID: 9829911 |
| Germline mutations detected in the von Hippel-Lindau disease tumor suppressor gene by Southern blot and direct genomic DNA sequencing. | Li C | Human mutation | 1998 | PMID: 9452032 |
| 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 |
| Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations. | Maher ER | Journal of medical genetics | 1996 | PMID: 8730290 |
| Somatic von Hippel-Lindau mutation in clear cell papillary cystadenoma of the epididymis. | Gilcrease MZ | Human pathology | 1995 | PMID: 8522307 |
| Identification of the promoter of the human von Hippel-Lindau disease tumor suppressor gene. | Kuzmin I | Oncogene | 1995 | PMID: 7784063 |
| Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. | Chen F | Human mutation | 1995 | PMID: 7728151 |
| A novel mutation in the von Hippel-Lindau gene. | Loeb DB | Human molecular genetics | 1994 | PMID: 7987327 |
| Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. | Crossey PA | Human molecular genetics | 1994 | PMID: 7987306 |
| http://docm.genome.wustl.edu/variants/ENST00000256474:c.481C>T | - | - | - | - |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VHL | - | - | - | - |
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Text-mined citations for rs5030818 ...
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Record last updated Oct 27, 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.