ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.242C>T (p.Pro81Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000551.4(VHL):c.242C>T (p.Pro81Leu)
Variation ID: 36899 Accession: VCV000036899.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10142089 (GRCh38) [ NCBI UCSC ] 3: 10183773 (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 Apr 4, 2013 Aug 4, 2024 Jan 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.242C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Pro81Leu missense NM_001354723.2:c.242C>T NP_001341652.1:p.Pro81Leu missense NM_198156.3:c.242C>T NP_937799.1:p.Pro81Leu missense NC_000003.12:g.10142089C>T NC_000003.11:g.10183773C>T NG_008212.3:g.5455C>T LRG_322:g.5455C>T LRG_322t1:c.242C>T LRG_322p1:p.Pro81Leu - Protein change
- P81L
- Other names
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- Canonical SPDI
- NC_000003.12:10142088:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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VHL | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
829 | 1994 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2023 | RCV000030582.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 9, 2024 | RCV000129974.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 27, 2023 | RCV001034657.6 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 13, 2022 | RCV001547784.20 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 24, 2023 | RCV003460493.2 |
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
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Dec 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Chuvash polycythemia
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004208788.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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likely pathogenic
(Aug 18, 2011)
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criteria provided, single submitter
Method: curation
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Von Hippel-Lindau Syndrome
(autosomal dominant)
Affected status: yes
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053258.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2022 |
Comment:
Converted during submission to Likely pathogenic.
Number of individuals with the variant: 1
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Likely pathogenic
(Apr 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001767572.3
First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023 |
Comment:
Observed in individuals with isolated pheochromocytoma and/or paraganglioma and no other features of von Hippel Lindau syndrome (Castellano 2006, Piccini 2012, Kim 2014, ClinVar SCV000553390.2); … (more)
Observed in individuals with isolated pheochromocytoma and/or paraganglioma and no other features of von Hippel Lindau syndrome (Castellano 2006, Piccini 2012, Kim 2014, ClinVar SCV000553390.2); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.455C>T, p.Pro152Leu, and p.Pro122Leu; This variant is associated with the following publications: (PMID: 24446253, 27730413, 29946849, 22241717, 17102082, 24134185, 21389259, 31589614) (less)
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Pathogenic
(Dec 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Chuvash polycythemia
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000553390.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the VHL protein (p.Pro81Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the VHL protein (p.Pro81Leu). This variant is present in population databases (rs193922608, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of von Hippel-Lindau disease (type 2C: pheochromocytoma and paraganglioma) (PMID: 17102082, 21389259, 22241717, 24134185, 27730413; Invitae). ClinVar contains an entry for this variant (Variation ID: 36899). 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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Likely pathogenic
(Feb 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002496778.16
First in ClinVar: Apr 08, 2022 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Mar 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV004183372.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
ACMG classification criteria: PS3, PS4, PM2, PP3
Geographic origin: Brazil
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Likely Pathogenic
(Apr 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004841640.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces proline with leucine at codon 81 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces proline with leucine at codon 81 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with VHL-associated tumor or have a VHL diagnosis (PMID: 17102082, 21389259, 22241717, 24134185, 33219105). This variant has been identified in 1/229958 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Jan 09, 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: SCV000184798.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.P81L variant (also known as c.242C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide … (more)
The p.P81L variant (also known as c.242C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 242. The proline at codon 81 is replaced by leucine, an amino acid with very few similar properties. This alteration has been reported in multiple individuals with diagnoses consistent with of von Hippel-Lindau syndrome (VHL), but not clearly meeting clinical diagnostic criteria; including an individual with a right carotid body paraganglioma (Piccini V et al. Endocr Relat Cancer. 2012 Apr 10;19(2):149-55), a patient with a left para-adrenal paraganglioma (Castellano M et al. Ann N Y Acad Sci. 2006 Aug;1073:156-65), an individual diagnosed with VHL type 2C (Formenti F et al. FASEB J. 2011 Jun;25(6):2001-11), and an individual with pheochromocytoma at age 16 (Kim JH et al. Clin Genet, 2014 Nov;86:482-6). Further, another alteration at this codon, p.P81S (c.241C>T) has been described both as a low-penetrance mutation in VHL type 1 families (Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67:758-62; Glavac D et al. Hum. Genet. 1996 Sep;98:271-80; Hes FJ et al. J. Med. Genet. 2000 Dec;37:939-43; Kondo K et al. Hum. Mol. Genet. 1995 Dec;4:2233-7; Yoshida M et al. Jpn J Cancer Res. 2000 Feb;90:204-212; Zbar B et al. Hum. Mutat. 1996;8:348-57; Alosi D et al. Curr. Genomics. 2017 Feb;18:93-103) and as a nonpathogenic alteration (Erlic Z et al. J Clin Endocrinol Metab. 2010 Jan;95:308-13). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, individuals may not present with classic von Hippel-Lindau syndrome. Clinical correlation is advised. (less)
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Likely 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: unknown
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000264681.1
First in ClinVar: Mar 08, 2016 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 10
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Likely pathogenic
(Feb 21, 2022)
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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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Clinical Genomics Labs, University Health Network
Accession: SCV002601728.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Characteristics of germline mutations in Korean patients with pheochromocytoma/paraganglioma. | Kim JH | Journal of medical genetics | 2022 | PMID: 33219105 |
Cancer Susceptibility Genetic Testing in a High-Risk Cohort of Urban Ashkenazi Jewish Individuals. | Nielsen SM | Journal of genetic counseling | 2018 | PMID: 29946849 |
Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of the VHL Mutation p.P81S (c.241C>T). | Alosi D | Current genomics | 2017 | PMID: 28503092 |
Presented Abstracts from the Thirty Fifth Annual Education Conference of the National Society of Genetic Counselors (Seattle, WA, September 2016). | - | Journal of genetic counseling | 2016 | PMID: 27730413 |
Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate. | Darbro BW | PloS one | 2016 | PMID: 26934580 |
Germline mutations and genotype-phenotype correlations in patients with apparently sporadic pheochromocytoma/paraganglioma in Korea. | Kim JH | Clinical genetics | 2014 | PMID: 24134185 |
Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. | Piccini V | Endocrine-related cancer | 2012 | PMID: 22241717 |
Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation. | Formenti F | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2011 | PMID: 21389259 |
Denaturing high performance liquid chromatography detection of SDHB, SDHD, and VHL germline mutations in pheochromocytoma. | Meyer-Rochow GY | The Journal of surgical research | 2009 | PMID: 19215943 |
Recent insights into the molecular pathogenesis of pheochromocytoma and paraganglioma. | Nakamura E | Endocrine pathology | 2006 | PMID: 17159241 |
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 |
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Text-mined citations for rs193922608 ...
HelpRecord last updated Sep 08, 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.