Variant summary: This c.485G>T affects a conserved nucleotide, resulting in amino acid change from Cys to Phe in alfa domain of VHL protein. 4/4 in-silico tools predict this variant to be damaging. The residue p.Cys162 is reported to directly contact with elongins and functional assays show that this variant abrogates the binding to elongin/Cul2 (Ohh_1999, Ohh_2000, Hansen_2002). The variant was also shown to abrogate the ubiquitination and binding to HIF and binding to E-cadherin (Ohh_2000, Hansen_2002, Evans_2007). These findings prove that this variant is functionally defective. This variant was found in 1/121234 control chromosomes including the broad and large populations from ExAC at a frequency of 0.0000082, which is lower than the maximal expected frequency of a pathogenic allele (0.0000208). This variant has been found in at least six independent VHL patients/families. One clinical lab (via ClinVar) has classified this variant as pathogenic. Other likely pathogenic variants (namely, p.C162R, p.C162W, and p.C162Y. p.Cys162TrpfsX12, etc.) have also been reported at this p.C162 residue, suggesting that this codon is likely to be a mutational hot-spot. Taken together, this variant has been classified as a Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.485G>T (p.Cys162Phe)
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.
(5)
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
5
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.485G>T (p.Cys162Phe)
Variation ID: 43604 Accession: VCV000043604.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10149808 (GRCh38) [ NCBI UCSC ] 3: 10191492 (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 Mar 8, 2016 Feb 28, 2024 Oct 18, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000551.4:c.485G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Cys162Phe missense NM_001354723.2:c.*39G>T 3 prime UTR NM_198156.3:c.362G>T NP_937799.1:p.Cys121Phe missense NC_000003.12:g.10149808G>T NC_000003.11:g.10191492G>T NG_008212.3:g.13174G>T NG_046756.1:g.7570G>T LRG_322:g.13174G>T LRG_322t1:c.485G>T LRG_322p1:p.Cys162Phe P40337:p.Cys162Phe - Protein change
- C162F, C121F
- Other names
- -
- Canonical SPDI
- NC_000003.12:10149807:G: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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- 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 (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 18, 2023 | RCV000036548.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 27, 2022 | RCV002513389.3 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Feb 04, 2016)
|
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: SCV000697522.1
First in ClinVar: Mar 08, 2016 Last updated: Mar 08, 2016 |
Comment:
Variant summary: This c.485G>T affects a conserved nucleotide, resulting in amino acid change from Cys to Phe in alfa domain of VHL protein. 4/4 in-silico … (more)
Variant summary: This c.485G>T affects a conserved nucleotide, resulting in amino acid change from Cys to Phe in alfa domain of VHL protein. 4/4 in-silico tools predict this variant to be damaging. The residue p.Cys162 is reported to directly contact with elongins and functional assays show that this variant abrogates the binding to elongin/Cul2 (Ohh_1999, Ohh_2000, Hansen_2002). The variant was also shown to abrogate the ubiquitination and binding to HIF and binding to E-cadherin (Ohh_2000, Hansen_2002, Evans_2007). These findings prove that this variant is functionally defective. This variant was found in 1/121234 control chromosomes including the broad and large populations from ExAC at a frequency of 0.0000082, which is lower than the maximal expected frequency of a pathogenic allele (0.0000208). This variant has been found in at least six independent VHL patients/families. One clinical lab (via ClinVar) has classified this variant as pathogenic. Other likely pathogenic variants (namely, p.C162R, p.C162W, and p.C162Y. p.Cys162TrpfsX12, etc.) have also been reported at this p.C162 residue, suggesting that this codon is likely to be a mutational hot-spot. Taken together, this variant has been classified as a Pathogenic. (less)
|
|
|
Pathogenic
(Jun 27, 2022)
|
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: SCV003525020.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 10878807, 11331612, 19228690). … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 10878807, 11331612, 19228690). 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: 43604). This variant is also known as c.698G>T. This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 9452032, 10458336, 20064270). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 162 of the VHL protein (p.Cys162Phe). (less)
|
|
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Pathogenic
(Oct 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV004171480.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Comment:
The VHL c.485G>T (p.Cys162Phe) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious … (more)
The VHL c.485G>T (p.Cys162Phe) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies indicate that this variant disrupts VHL protein function and impairs ability to bind to hypoxia-inducible factor (HIF) (PMID: 34004371, 10878807, 11331612, 11865071, 17060462, 19228690). This variant has been reported in individuals and families with Von Hippel Lindau-related cancers (PMID: 9452032, 20064270). In summary, this variant meets criteria to be classified as pathogenic. (less)
|
|
|
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: SCV000264759.1
First in ClinVar: Mar 08, 2016 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 5
|
|
|
Pathogenic
(Apr 18, 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: SCV000060203.5
First in ClinVar: May 03, 2013 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 1
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 10878807, 11331612, 19228690). 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: 43604). This variant is also known as c.698G>T. This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 9452032, 10458336, 20064270). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 162 of the VHL protein (p.Cys162Phe).
Comment:
The VHL c.485G>T (p.Cys162Phe) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies indicate that this variant disrupts VHL protein function and impairs ability to bind to hypoxia-inducible factor (HIF) (PMID: 34004371, 10878807, 11331612, 11865071, 17060462, 19228690). This variant has been reported in individuals and families with Von Hippel Lindau-related cancers (PMID: 9452032, 20064270). In summary, this variant meets criteria to be classified as pathogenic.
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:
Variant summary: This c.485G>T affects a conserved nucleotide, resulting in amino acid change from Cys to Phe in alfa domain of VHL protein. 4/4 in-silico tools predict this variant to be damaging. The residue p.Cys162 is reported to directly contact with elongins and functional assays show that this variant abrogates the binding to elongin/Cul2 (Ohh_1999, Ohh_2000, Hansen_2002). The variant was also shown to abrogate the ubiquitination and binding to HIF and binding to E-cadherin (Ohh_2000, Hansen_2002, Evans_2007). These findings prove that this variant is functionally defective. This variant was found in 1/121234 control chromosomes including the broad and large populations from ExAC at a frequency of 0.0000082, which is lower than the maximal expected frequency of a pathogenic allele (0.0000208). This variant has been found in at least six independent VHL patients/families. One clinical lab (via ClinVar) has classified this variant as pathogenic. Other likely pathogenic variants (namely, p.C162R, p.C162W, and p.C162Y. p.Cys162TrpfsX12, etc.) have also been reported at this p.C162 residue, suggesting that this codon is likely to be a mutational hot-spot. Taken together, this variant has been classified as a Pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 10878807, 11331612, 19228690). 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: 43604). This variant is also known as c.698G>T. This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 9452032, 10458336, 20064270). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 162 of the VHL protein (p.Cys162Phe).
Comment:
The VHL c.485G>T (p.Cys162Phe) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies indicate that this variant disrupts VHL protein function and impairs ability to bind to hypoxia-inducible factor (HIF) (PMID: 34004371, 10878807, 11331612, 11865071, 17060462, 19228690). This variant has been reported in individuals and families with Von Hippel Lindau-related cancers (PMID: 9452032, 20064270). In summary, this variant meets criteria to be classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Uptake of genetic testing and long-term tumor surveillance in von Hippel-Lindau disease. | Rasmussen A | BMC medical genetics | 2010 | PMID: 20064270 |
| VHL mutations linked to type 2C von Hippel-Lindau disease cause extensive structural perturbations in pVHL. | Knauth K | The Journal of biological chemistry | 2009 | PMID: 19228690 |
| A novel von Hippel-Lindau point mutation presents as apparently sporadic pheochromocytoma. | Rich TA | Cancer investigation | 2008 | PMID: 18584357 |
| Hypoxia-inducible factor-2alpha regulates the expression of TRAIL receptor DR5 in renal cancer cells. | Mahajan S | Carcinogenesis | 2008 | PMID: 18544564 |
| VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. | Evans AJ | Molecular and cellular biology | 2007 | PMID: 17060462 |
| Diverse effects of mutations in exon II of the von Hippel-Lindau (VHL) tumor suppressor gene on the interaction of pVHL with the cytosolic chaperonin and pVHL-dependent ubiquitin ligase activity. | Hansen WJ | Molecular and cellular biology | 2002 | PMID: 11865071 |
| von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. | Hoffman MA | Human molecular genetics | 2001 | PMID: 11331612 |
| Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. | Ohh M | Nature cell biology | 2000 | PMID: 10878807 |
| 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 and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. | Walther MM | The Journal of urology | 1999 | PMID: 10458336 |
| 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 |
| 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 rs397516444 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.