Variant summary: VHL c.266T>C (p.Leu89Pro) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 225978 control chromosomes (gnomAD). c.266T>C has been reported in the literature in multiple individuals and families affected with Von Hippel-Lindau Syndrome (e.g. Crossey_1994, Glavac_1996, Chacon-Camacho_2010, Liu_2018). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.266T>C (p.Leu89Pro)
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.266T>C (p.Leu89Pro)
Variation ID: 182979 Accession: VCV000182979.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10142113 (GRCh38) [ NCBI UCSC ] 3: 10183797 (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 Mar 26, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000551.4:c.266T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Leu89Pro missense NM_001354723.2:c.266T>C NP_001341652.1:p.Leu89Pro missense NM_198156.3:c.266T>C NP_937799.1:p.Leu89Pro missense NC_000003.12:g.10142113T>C NC_000003.11:g.10183797T>C NG_008212.3:g.5479T>C LRG_322:g.5479T>C LRG_322t1:c.266T>C LRG_322p1:p.Leu89Pro P40337:p.Leu89Pro - Protein change
- L89P
- Other names
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- Canonical SPDI
- NC_000003.12:10142112:T:C
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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 (1) |
criteria provided, single submitter
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Mar 26, 2024 | RCV000161087.4 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 20, 2024 | RCV000208869.3 | |
| Pathogenic (1) |
criteria provided, single submitter
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Nov 21, 2023 | RCV000817709.5 |
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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Pathogenic
(Dec 21, 2021)
|
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: SCV002051311.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: VHL c.266T>C (p.Leu89Pro) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the … (more)
Variant summary: VHL c.266T>C (p.Leu89Pro) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 225978 control chromosomes (gnomAD). c.266T>C has been reported in the literature in multiple individuals and families affected with Von Hippel-Lindau Syndrome (e.g. Crossey_1994, Glavac_1996, Chacon-Camacho_2010, Liu_2018). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 21, 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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000958287.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 89 of the VHL protein (p.Leu89Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 89 of the VHL protein (p.Leu89Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7987306, 8707293, 11309459, 17024664, 20151405). It has also been observed to segregate with disease in related individuals. This variant is also known as 479T>C and Leu160Pro. ClinVar contains an entry for this variant (Variation ID: 182979). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 20, 2024)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004930927.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8707293, 20447124, 17024664, 31620170]. This … (more)
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8707293, 20447124, 17024664, 31620170]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Likely pathogenic
(Mar 26, 2024)
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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: SCV000276228.8
First in ClinVar: Feb 24, 2015 Last updated: Aug 11, 2024 |
Comment:
The p.L89P variant (also known as c.266T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide … (more)
The p.L89P variant (also known as c.266T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 266. The leucine at codon 89 is replaced by proline, an amino acid with similar properties. This variant has been reported in numerous VHL kindreds to date (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3:1303-8; Zbar B et al. Hum. Mutat. 1996;8:348-57; Glavac D et al. Hum. Genet. 1996 Sep;98:271-80; Webster AR et al. Arch. Ophthalmol. 1999 Mar;117:371-8; Klein B et al. Hum. Genet. 2001 May;108:376-84; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9; Rajasekaran R et al. Mamm. Genome. 2008 Sep;19:654-61; Nordstrom-O'Brien M et al. Hum. Mutat. 2010 May;31:521-37). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Feb 26, 2016)
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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: SCV000264689.1
First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016 |
Number of individuals with the variant: 3
|
Comment:
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 89 of the VHL protein (p.Leu89Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7987306, 8707293, 11309459, 17024664, 20151405). It has also been observed to segregate with disease in related individuals. This variant is also known as 479T>C and Leu160Pro. ClinVar contains an entry for this variant (Variation ID: 182979). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8707293, 20447124, 17024664, 31620170]. This variant is expected to disrupt protein structure [Myriad internal data].
Comment:
The p.L89P variant (also known as c.266T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 266. The leucine at codon 89 is replaced by proline, an amino acid with similar properties. This variant has been reported in numerous VHL kindreds to date (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3:1303-8; Zbar B et al. Hum. Mutat. 1996;8:348-57; Glavac D et al. Hum. Genet. 1996 Sep;98:271-80; Webster AR et al. Arch. Ophthalmol. 1999 Mar;117:371-8; Klein B et al. Hum. Genet. 2001 May;108:376-84; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9; Rajasekaran R et al. Mamm. Genome. 2008 Sep;19:654-61; Nordstrom-O'Brien M et al. Hum. Mutat. 2010 May;31:521-37). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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: VHL c.266T>C (p.Leu89Pro) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 225978 control chromosomes (gnomAD). c.266T>C has been reported in the literature in multiple individuals and families affected with Von Hippel-Lindau Syndrome (e.g. Crossey_1994, Glavac_1996, Chacon-Camacho_2010, Liu_2018). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 89 of the VHL protein (p.Leu89Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7987306, 8707293, 11309459, 17024664, 20151405). It has also been observed to segregate with disease in related individuals. This variant is also known as 479T>C and Leu160Pro. ClinVar contains an entry for this variant (Variation ID: 182979). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8707293, 20447124, 17024664, 31620170]. This variant is expected to disrupt protein structure [Myriad internal data].
Comment:
The p.L89P variant (also known as c.266T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 266. The leucine at codon 89 is replaced by proline, an amino acid with similar properties. This variant has been reported in numerous VHL kindreds to date (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3:1303-8; Zbar B et al. Hum. Mutat. 1996;8:348-57; Glavac D et al. Hum. Genet. 1996 Sep;98:271-80; Webster AR et al. Arch. Ophthalmol. 1999 Mar;117:371-8; Klein B et al. Hum. Genet. 2001 May;108:376-84; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9; Rajasekaran R et al. Mamm. Genome. 2008 Sep;19:654-61; Nordstrom-O'Brien M et al. Hum. Mutat. 2010 May;31:521-37). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel-Lindau Disease. | Hong B | Frontiers in genetics | 2019 | PMID: 31620170 |
| Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein. | Liu SJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29595810 |
| Clinical and molecular features of familial and sporadic cases of von Hippel-Lindau disease from Mexico. | Chacon-Camacho OF | Clinical & experimental ophthalmology | 2010 | PMID: 20447124 |
| Genetic analysis of von Hippel-Lindau disease. | Nordstrom-O'Brien M | Human mutation | 2010 | PMID: 20151405 |
| 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 |
| Genotype-phenotype correlations in von Hippel-Lindau disease. | Ong KR | Human mutation | 2007 | PMID: 17024664 |
| DHPLC-based germline mutation screening in the analysis of the VHL tumor suppressor gene: usefulness and limitations. | Klein B | Human genetics | 2001 | PMID: 11409863 |
| Reconsideration of biallelic inactivation of the VHL tumour suppressor gene in hemangioblastomas of the central nervous system. | Gläsker S | Journal of neurology, neurosurgery, and psychiatry | 2001 | PMID: 11309459 |
| 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 VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe. | Glavac D | Human genetics | 1996 | PMID: 8707293 |
| 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 |
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Text-mined citations for rs5030807 ...
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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.