This sequence change replaces proline with alanine at codon 86 of the VHL protein (p.Pro86Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 17102082, 27034144, 7728151, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.469C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 93327). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Pro86 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8634692, 9829912, 19464396, 27057652, 27527340, 11257211, 19408298). 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.
ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.256C>G (p.Pro86Ala)
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/Likely 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
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NM_000551.4(VHL):c.256C>G (p.Pro86Ala)
Variation ID: 93327 Accession: VCV000093327.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10142103 (GRCh38) [ NCBI UCSC ] 3: 10183787 (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 Mar 9, 2016 Aug 11, 2024 Jun 5, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000551.4:c.256C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Pro86Ala missense NM_001354723.2:c.256C>G NP_001341652.1:p.Pro86Ala missense NM_198156.3:c.256C>G NP_937799.1:p.Pro86Ala missense NC_000003.12:g.10142103C>G NC_000003.11:g.10183787C>G NG_008212.3:g.5469C>G LRG_322:g.5469C>G LRG_322t1:c.256C>G LRG_322p1:p.Pro86Ala P40337:p.Pro86Ala - Protein change
- P86A
- Other names
- -
- Canonical SPDI
- NC_000003.12:10142102:C: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
Help
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
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. |
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| VHL | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
832 | 2004 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, single submitter
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Jan 29, 2016 | RCV000079208.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 2, 2013 | RCV000723702.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 12, 2019 | RCV001227827.10 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 5, 2024 | RCV004686575.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Jul 02, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000111078.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
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Pathogenic
(Nov 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Erythrocytosis, familial, 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001400203.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
This sequence change replaces proline with alanine at codon 86 of the VHL protein (p.Pro86Ala). The proline residue is highly conserved and there is a … (more)
This sequence change replaces proline with alanine at codon 86 of the VHL protein (p.Pro86Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 17102082, 27034144, 7728151, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.469C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 93327). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Pro86 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8634692, 9829912, 19464396, 27057652, 27527340, 11257211, 19408298). 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)
|
|
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Likely pathogenic
(Jun 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005179646.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The p.P86A variant (also known as c.256C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide … (more)
The p.P86A variant (also known as c.256C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 256. The proline at codon 86 is replaced by alanine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals with clinical findings of von Hippel Lindau (VHL) (Ambry internal data; Chen F et al. Hum Mutat, 1995;5:66-75; Castellano M et al. Ann N Y Acad Sci, 2006 Aug;1073:156-65; Ferrara AM et al. Cancer Res Treat, 2016 Oct;48:1438-1442; Reich M et al. Acta Ophthalmol, 2021 Dec;99:e1492-e1500; Morlacchi LC et al. ERJ Open Res, 2023 Nov;9:). Of note, this alteration is also known as 469C>G in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
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Likely pathogenic
(Jan 29, 2016)
|
criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697489.1
First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016 |
Comment:
Variant summary: This c.256C>G variant affects a conserved nucleotide, resulting in amino acid change from Pro to Ala in HIFalfa domain of VHL protein. 4/4 … (more)
Variant summary: This c.256C>G variant affects a conserved nucleotide, resulting in amino acid change from Pro to Ala in HIFalfa domain of VHL protein. 4/4 in-silico tools predict this variant to be damaging. This variant was found in 2/102226 control chromosomes including the broad and large population from ExAC at a frequency of 0.0000196, which is lower than the maximal expected frequency of a pathogenic allele (0.0000208) in this gene. In literature, this variant has been reported in five independent patients with Von Hippel-Lindau disease or related cancers. Other missense changes at this codon are also reported in association VHL disease, namely p.P86R, p.P86L and p.P86S, suggesting that this codon is likely to be a mutational hot-spot. One clinical lab (via ClinVar) and one reputable database classify this variant as pathogenic. Taken together, this variant is currently classified as Likely Pathogenic. (less)
|
|
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Likely pathogenic
(Feb 26, 2016)
|
no assertion criteria provided
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: SCV000264683.1
First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016 |
Number of individuals with the variant: 3
|
Comment:
Comment:
The p.P86A variant (also known as c.256C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 256. The proline at codon 86 is replaced by alanine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals with clinical findings of von Hippel Lindau (VHL) (Ambry internal data; Chen F et al. Hum Mutat, 1995;5:66-75; Castellano M et al. Ann N Y Acad Sci, 2006 Aug;1073:156-65; Ferrara AM et al. Cancer Res Treat, 2016 Oct;48:1438-1442; Reich M et al. Acta Ophthalmol, 2021 Dec;99:e1492-e1500; Morlacchi LC et al. ERJ Open Res, 2023 Nov;9:). Of note, this alteration is also known as 469C>G in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
Variant summary: This c.256C>G variant affects a conserved nucleotide, resulting in amino acid change from Pro to Ala in HIFalfa domain of VHL protein. 4/4 in-silico tools predict this variant to be damaging. This variant was found in 2/102226 control chromosomes including the broad and large population from ExAC at a frequency of 0.0000196, which is lower than the maximal expected frequency of a pathogenic allele (0.0000208) in this gene. In literature, this variant has been reported in five independent patients with Von Hippel-Lindau disease or related cancers. Other missense changes at this codon are also reported in association VHL disease, namely p.P86R, p.P86L and p.P86S, suggesting that this codon is likely to be a mutational hot-spot. One clinical lab (via ClinVar) and one reputable database classify this variant as pathogenic. Taken together, this variant is currently classified as Likely 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:
This sequence change replaces proline with alanine at codon 86 of the VHL protein (p.Pro86Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 17102082, 27034144, 7728151, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.469C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 93327). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Pro86 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8634692, 9829912, 19464396, 27057652, 27527340, 11257211, 19408298). 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:
The p.P86A variant (also known as c.256C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 256. The proline at codon 86 is replaced by alanine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals with clinical findings of von Hippel Lindau (VHL) (Ambry internal data; Chen F et al. Hum Mutat, 1995;5:66-75; Castellano M et al. Ann N Y Acad Sci, 2006 Aug;1073:156-65; Ferrara AM et al. Cancer Res Treat, 2016 Oct;48:1438-1442; Reich M et al. Acta Ophthalmol, 2021 Dec;99:e1492-e1500; Morlacchi LC et al. ERJ Open Res, 2023 Nov;9:). Of note, this alteration is also known as 469C>G in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
Variant summary: This c.256C>G variant affects a conserved nucleotide, resulting in amino acid change from Pro to Ala in HIFalfa domain of VHL protein. 4/4 in-silico tools predict this variant to be damaging. This variant was found in 2/102226 control chromosomes including the broad and large population from ExAC at a frequency of 0.0000196, which is lower than the maximal expected frequency of a pathogenic allele (0.0000208) in this gene. In literature, this variant has been reported in five independent patients with Von Hippel-Lindau disease or related cancers. Other missense changes at this codon are also reported in association VHL disease, namely p.P86R, p.P86L and p.P86S, suggesting that this codon is likely to be a mutational hot-spot. One clinical lab (via ClinVar) and one reputable database classify this variant as pathogenic. Taken together, this variant is currently classified as Likely Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Idiopathic interstitial pneumonia in a patient with von Hippel-Lindau syndrome: a first case. | Morlacchi LC | ERJ open research | 2023 | PMID: 38020566 |
| Genotype-phenotype correlation in von Hippel-Lindau disease. | Reich M | Acta ophthalmologica | 2021 | PMID: 33720516 |
| Clinical and molecular characteristics of East Asian patients with von Hippel-Lindau syndrome. | Wong M | Chinese journal of cancer | 2016 | PMID: 27527340 |
| Germline mutations in the VHL gene associated with 3 different renal lesions in a Chinese von Hippel-Lindau disease family. | Yuan P | Cancer biology & therapy | 2016 | PMID: 27057652 |
| Coexistence of VHL Disease and CPT2 Deficiency: A Case Report. | Ferrara AM | Cancer research and treatment | 2016 | PMID: 27034144 |
| Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma. | Taylor C | International journal of oncology | 2012 | PMID: 22825683 |
| Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease. | Jonasch E | Annals of oncology : official journal of the European Society for Medical Oncology | 2011 | PMID: 22105611 |
| Analysis of VHL Gene Alterations and their Relationship to Clinical Parameters in Sporadic Conventional Renal Cell Carcinoma. | Young AC | Clinical cancer research : an official journal of the American Association for Cancer Research | 2009 | PMID: 19996202 |
| Germline mutations in the von Hippel-Lindau gene in Italian patients. | Ciotti P | European journal of medical genetics | 2009 | PMID: 19464396 |
| 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 |
| Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia. | van Rooijen E | Blood | 2009 | PMID: 19304954 |
| Computational detection of deleterious SNPs and their effect on sequence and structural level of the VHL gene. | Rajasekaran R | Mammalian genome : official journal of the International Mammalian Genome Society | 2008 | PMID: 18836774 |
| Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients. | Castellano M | Annals of the New York Academy of Sciences | 2006 | PMID: 17102082 |
| Is the P25L a "real" VHL mutation? | Rothberg PG | Molecular diagnosis : a journal devoted to the understanding of human disease through the clinical application of molecular biology | 2001 | PMID: 11257211 |
| Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. | Olschwang S | Human mutation | 1998 | PMID: 9829912 |
| Genotype-phenotype correlations in von Hippel-Lindau disease. | Neumann HP | Journal of internal medicine | 1998 | PMID: 9681856 |
| 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 (VHL) gene in Japanese VHL. Clinical Research Group for VHL in Japan. | - | Human molecular genetics | 1995 | PMID: 8634692 |
| Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. | Chen F | Human mutation | 1995 | PMID: 7728151 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VHL | - | - | - | - |
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Text-mined citations for rs398123481 ...
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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 Nov 10, 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.