ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.250G>C (p.Val84Leu)
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.250G>C (p.Val84Leu)
Variation ID: 229860 Accession: VCV000229860.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10142097 (GRCh38) [ NCBI UCSC ] 3: 10183781 (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 May 29, 2016 Feb 28, 2024 Mar 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.250G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Val84Leu missense NM_001354723.2:c.250G>C NP_001341652.1:p.Val84Leu missense NM_198156.3:c.250G>C NP_937799.1:p.Val84Leu missense NC_000003.12:g.10142097G>C NC_000003.11:g.10183781G>C NG_008212.3:g.5463G>C LRG_322:g.5463G>C LRG_322t1:c.250G>C LRG_322p1:p.Val84Leu P40337:p.Val84Leu - Protein change
- V84L
- Other names
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- Canonical SPDI
- NC_000003.12:10142096:G: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
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The frequency of the allele represented by this VCV record.
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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 |
802 | 1957 |
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
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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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Pathogenic (1) |
criteria provided, single submitter
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Jan 2, 2015 | RCV000216720.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2018 | RCV000588802.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 26, 2023 | RCV001382229.6 |
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
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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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Pathogenic
(Jan 29, 2016)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697488.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: This c.250G>C variant affects a conserved nucleotide, resulting in amino acid change from Val to Leu in beta domain of VHL protein. 2/4 … (more)
Variant summary: This c.250G>C variant affects a conserved nucleotide, resulting in amino acid change from Val to Leu in beta domain of VHL protein. 2/4 in-silico tools predict this variant to be damaging. This variant was not found in approximately 99326 chromosomes from ExAC. This variant has been reported in one VHL patient as a de novo occurrence (Leonardi_2011) and in other two VHL patients as somatic occurrence (Burnichon_2011, Pena-Llopis_2013). Another nucleotide change c.250G>T leading to the same amino acid change is a known pathogenic variant, strongly supporting that this nucleotide change is also pathogenic. Functional studies show that p.V84L mutant impairs in forming stable pVHL-ElonginC-ElonginB (VCB) complexes which is implicated in the disease (Knauth_2009). Taken together, this variant has been classified as a Pathogenic. (less)
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Pathogenic
(Aug 01, 2018)
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criteria provided, single submitter
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: SCV000897790.1
First in ClinVar: Apr 17, 2019 Last updated: Apr 17, 2019 |
Number of individuals with the variant: 3
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Pathogenic
(Jan 02, 2015)
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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: SCV000273215.6
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.V84L pathogenic mutation (also known as c.250G>C and p.V155L), located in coding exon 1 of the VHL gene, results from a G to C … (more)
The p.V84L pathogenic mutation (also known as c.250G>C and p.V155L), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 250. The valine at codon 84 is replaced by leucine, an amino acid with highly similar properties. This variant has been reported in apparent de novo transmission in one individual with pheochromocytoma, out of a cohort of 426 unrelated individuals presenting with clinical suspicion for VHL (Leonardi E et al. Ann. Hum. Genet. 2011 Jul; 75(4):483-96). Additionally, a well described mutation at the same position (c.250G>T), also resulting in the valine at codon 84 being replaced by leucine, has been identified in a number of families with early-onset pheochromocytomas (VHL type 2C) (Crossey PA et al. J. Med. Genet.1995 Nov; 32(11):885-6; Abbott MA et al. Am. J. Med. Genet. A 2006 Apr; 140(7):685-90). Based on the available evidence, p.V84L is classified as a pathogenic mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Mar 26, 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: SCV001580901.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 11331612, 11331613, 12510195, 19228690, 19602254, 21791076). 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: 229860). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 8592333, 11409863, 16502427, 19215943, 19270817, 25078357). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the VHL protein (p.Val84Leu). (less)
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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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BAP1 loss defines a new class of renal cell carcinoma. | Peña-Llopis S | Nature genetics | 2012 | PMID: 22683710 |
Inactivation of the von Hippel-Lindau tumour suppressor gene induces Neuromedin U expression in renal cancer cells. | Harten SK | Molecular cancer | 2011 | PMID: 21791076 |
Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. | Burnichon N | Human molecular genetics | 2011 | PMID: 21784903 |
Identification and in silico analysis of novel von Hippel-Lindau (VHL) gene variants from a large population. | Leonardi E | Annals of human genetics | 2011 | PMID: 21463266 |
Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes. | Bangiyeva V | BMC cancer | 2009 | PMID: 19602254 |
Improved detection of germline mutations in Korean VHL patients by multiple ligation-dependent probe amplification analysis. | Cho HJ | Journal of Korean medical science | 2009 | PMID: 19270817 |
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 |
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 |
The von Hippel-Lindau (VHL) germline mutation V84L manifests as early-onset bilateral pheochromocytoma. | Abbott MA | American journal of medical genetics. Part A | 2006 | PMID: 16502427 |
Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. | Hergovich A | Nature cell biology | 2003 | PMID: 12510195 |
DHPLC-based germline mutation screening in the analysis of the VHL tumor suppressor gene: usefulness and limitations. | Klein B | Human genetics | 2001 | PMID: 11409863 |
Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. | Clifford SC | Human molecular genetics | 2001 | PMID: 11331613 |
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 |
Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma. | Crossey PA | Journal of medical genetics | 1995 | PMID: 8592333 |
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Text-mined citations for rs5030827 ...
HelpRecord last updated Mar 05, 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.