ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.257C>T (p.Pro86Leu)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000551.4(VHL):c.257C>T (p.Pro86Leu)
Variation ID: 182977 Accession: VCV000182977.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p25.3 3: 10142104 (GRCh38) [ NCBI UCSC ] 3: 10183788 (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 9, 2016 Aug 18, 2024 Jun 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000551.4:c.257C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Pro86Leu missense NM_001354723.2:c.257C>T NP_001341652.1:p.Pro86Leu missense NM_198156.3:c.257C>T NP_937799.1:p.Pro86Leu missense NC_000003.12:g.10142104C>T NC_000003.11:g.10183788C>T NG_008212.3:g.5470C>T LRG_322:g.5470C>T LRG_322t1:c.257C>T LRG_322p1:p.Pro86Leu P40337:p.Pro86Leu - Protein change
- P86L
- Other names
- NM_000551.4(VHL):c.257C>T
- Canonical SPDI
- NC_000003.12:10142103: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.
-
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 |
830 | 2000 |
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) |
reviewed by expert panel
|
Jun 25, 2024 | RCV000208836.5 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 7, 2021 | RCV000492524.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 18, 2024 | RCV001382230.7 |
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
(Jun 25, 2024)
|
reviewed by expert panel
Method: curation
|
Von Hippel-Lindau syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen VHL Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV005187312.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
Comment:
The variant NM_000551.4(VHL):c.257C>T (p.Pro86Leu) is a missense variant predicted to cause substitution of Proline by Leucine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This … (more)
The variant NM_000551.4(VHL):c.257C>T (p.Pro86Leu) is a missense variant predicted to cause substitution of Proline by Leucine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This is identified in over 10 probands meeting either Danish criteria for VHL, or harboring other consistent features with VHL. The total phenotype points is 7.5, which meets the VHL VCEP specification of PS4 (5-15 phenotype points) (PMIDs:7728151; 27527340; 29437867; 21463266). The variant has been reported to segregate with von Hippel Lindau syndrome in at least 7 affected family members from 2 families (PP1_Strong; PMID: 7728151). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024 Variant Approval Date 06/25/2024). (less)
|
|
Pathogenic
(Feb 02, 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: SCV000697492.1
First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016 |
Comment:
Variant summary: c.257C>T affects a conserved nucleotide, resulting in amino acid change from Pro to Leu. 4/4 in-silico tools predict this variant to be damaging. … (more)
Variant summary: c.257C>T affects a conserved nucleotide, resulting in amino acid change from Pro to Leu. 4/4 in-silico tools predict this variant to be damaging. This variant was not found in 102226 control chromosomes. This variant has been reported in multiple VHL pts with clear co-segregation of the variant with disease in the families. Variants P86A, P86R, and P86S are all listed as disease mutation in HGMD and have been reported in multiple publications, suggesting the codon 86 is a hypermutable amino acid and a hotspot for mutations. In addition, one clinical laboratory (via Clinvar) classified this variant as pathogenic. Taken together, this variant was classified as a Pathogenic. (less)
|
|
Pathogenic
(Jan 18, 2024)
|
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: SCV001580902.4
First in ClinVar: May 10, 2021 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 86 of the VHL protein (p.Pro86Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 86 of the VHL protein (p.Pro86Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau (VHL) syndrome (PMID: 7728151, 27527340; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.470C>T, p.Pro157Leu. ClinVar contains an entry for this variant (Variation ID: 182977). 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%. 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). 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
(Oct 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000580955.6
First in ClinVar: Jul 01, 2017 Last updated: May 01, 2024 |
Comment:
The p.P86L pathogenic mutation (also known as c.257C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at … (more)
The p.P86L pathogenic mutation (also known as c.257C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 257. The proline at codon 86 is replaced by leucine, an amino acid with very few similar properties. This pathogenic mutation has been found in multiple individuals meeting clinical criteria for Von Hippel-Lindau syndrome with symptoms including retinal angiomas, CNS hemangioblastomas, renal cell carcinoma, and pancreatic cysts/tumors (Chen F et al. Hum. Mutat. 1995; 5(1):66-75; Kondo et al. Hum. Mol. Genet. 1995 Dec;4(12):2233-7; Yoshida M et al. Jpn. J. Cancer Res. 2000 Feb; 91(2):204-12; Ong KR et al. Hum. Mutat. 2007 Feb;28(2):143-9; Zhang J et al J. Cancer Res. Clin. Oncol. 2008 Nov;134(11):1211-8; Wong M et al. Chin J Cancer. 2016 Aug;35:79). Three unique alterations located at the same position, p.P86A, p.P86S, and p.P86R, have each been documented in the literature as having an association with Von Hippel-Lindau syndrome suggesting this codon may represent a mutation hotspot. Of note, the p.P86L (c.257C>T) alteration has also been reported as p.P157L (c.470C>T) in some literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (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: SCV000264685.1
First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016 |
Number of individuals with the variant: 8
|
|
Likely pathogenic
(Aug 24, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
|
Clinical Genomics Labs, University Health Network
Accession: SCV001950152.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
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 |
---|---|---|---|---|
Central Nervous System Hemangioblastoma in a Pediatric Patient Associated With Von Hippel-Lindau Disease: A Case Report and Literature Review. | Yang B | Frontiers in oncology | 2021 | PMID: 34109129 |
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 |
Molecular dissection of the VHL gene in solitary capillary hemangioblastoma of the central nervous system. | Muscarella LA | Journal of neuropathology and experimental neurology | 2014 | PMID: 24335534 |
Identification of 3 novel VHL germ-line mutations in Danish VHL patients. | Dandanell M | BMC medical genetics | 2012 | PMID: 22799452 |
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 |
A novel von Hippel-Lindau point mutation presents as apparently sporadic pheochromocytoma. | Rich TA | Cancer investigation | 2008 | PMID: 18584357 |
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 |
Germline VHL gene mutations in three Serbian families with von Hippel-Lindau disease. | Stanojevic BR | Neoplasma | 2007 | PMID: 17688370 |
[Germ line mutations in Chinese kindreds with von Hippel-Lindau syndrome]. | Zhang J | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2007 | PMID: 17407064 |
Genotype-phenotype correlations in von Hippel-Lindau disease. | Ong KR | Human mutation | 2007 | PMID: 17024664 |
Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. | Banks RE | Cancer research | 2006 | PMID: 16488999 |
Molecular genetic analysis of von Hippel-Lindau disease by denaturing high-performance liquid chromatography. | Menegatti E | Contributions to nephrology | 2001 | PMID: 11688398 |
Germ-line mutation analysis in patients with von Hippel-Lindau disease in Japan: an extended study of 77 families. | Yoshida M | Japanese journal of cancer research : Gann | 2000 | PMID: 10761708 |
A family with hydrocephalus as a complication of cerebellar hemangioblastoma: identification of Pro157Leu mutation in the VHL gene. | Fukino K | Journal of human genetics | 2000 | PMID: 10697963 |
Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC. | Gallou C | Human mutation | 1999 | PMID: 10408776 |
Trichloroethylene exposure and specific somatic mutations in patients with renal cell carcinoma. | Brauch H | Journal of the National Cancer Institute | 1999 | PMID: 10340905 |
Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. | Olschwang S | Human mutation | 1998 | PMID: 9829912 |
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 |
Cellular proteins that bind the von Hippel-Lindau disease gene product: mapping of binding domains and the effect of missense mutations. | Kishida T | Cancer research | 1995 | PMID: 7553625 |
Mutations of the VHL tumour suppressor gene in renal carcinoma. | Gnarra JR | Nature genetics | 1994 | PMID: 7915601 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/318690ae-2743-4195-8d9b-e2e84ff94494 | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs730882034 ...
HelpRecord 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.