ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.245G>T (p.Arg82Leu)
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.245G>T (p.Arg82Leu)
Variation ID: 526675 Accession: VCV000526675.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10142092 (GRCh38) [ NCBI UCSC ] 3: 10183776 (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 28, 2018 Feb 28, 2024 Mar 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.245G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Arg82Leu missense NM_001354723.2:c.245G>T NP_001341652.1:p.Arg82Leu missense NM_198156.3:c.245G>T NP_937799.1:p.Arg82Leu missense NC_000003.12:g.10142092G>T NC_000003.11:g.10183776G>T NG_008212.3:g.5458G>T LRG_322:g.5458G>T LRG_322t1:c.245G>T LRG_322p1:p.Arg82Leu - Protein change
- R82L
- Other names
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- Canonical SPDI
- NC_000003.12:10142091:G: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.
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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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Aug 17, 2019 | RCV000631271.8 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 3, 2023 | RCV001553666.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 10, 2023 | RCV002448934.2 |
Submissions - Germline
Classification
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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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Likely pathogenic
(Jul 08, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001774603.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Variant summary: VHL c.245G>T (p.Arg82Leu) results in a non-conservative amino acid change located in the VHL disease tumor suppressor, beta/alpha domain (IPR022772) of the encoded … (more)
Variant summary: VHL c.245G>T (p.Arg82Leu) results in a non-conservative amino acid change located in the VHL disease tumor suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 229092 control chromosomes. c.245G>T has been reported in the literature in the setting of bilateral pheochromocytoma in the absence of other tumors reported in patients with von Hippel-Lindau disease (example, Mary John_2013, Amini_2013) and a in report of custom multigene panel of 17 paraganglioma and pheochromocytoma (PPGL) genes (Ben Amin_2019). The variant segregated with bilateral pheochromocytoma in one family (Mary John_2013) and originated de-novo in the other (Amini_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Although several reports describing an impact of a different missense variant located at this codon, namely p.Arg82Pro as impacting VHL function have been published, supporting the relevance of this Arginine residue. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing overlapping clinical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Mar 10, 2023)
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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: SCV002732297.2
First in ClinVar: Nov 29, 2022 Last updated: Apr 15, 2023 |
Comment:
The p.R82L variant (also known as c.245G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide … (more)
The p.R82L variant (also known as c.245G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 245. The arginine at codon 82 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals with VHL spectrum tumors, including a proband and two children all with bilateral pheochromocytomas and all positive for this variant (Amini Z et al. J. Pediatr. Endocrinol. Metab., 2013;26:369-72; Krauss T et al. Endocr. Relat. Cancer, 2018 09;25:783-793; Ebenazer A et al. Fam. Cancer, 2013 Sep;12:519-24; John AM et al. PLoS ONE, 2013 Apr;8:e61908; Penitenti F et al. Endocrine, 2021 Oct;74:180-187; Ambry internal data). Based on internal structural analysis, R82L is deleterious (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Likely pathogenic
(Mar 03, 2023)
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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
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Myriad Genetics, Inc.
Accession: SCV004019579.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23626751, 30877234, 23327821, 34036514]. … (more)
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23626751, 30877234, 23327821, 34036514]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Pathogenic
(Aug 17, 2019)
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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: SCV000752299.6
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Arg82Pro) has been reported to segregate with¬†von Hippel-Lindau … (more)
For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Arg82Pro) has been reported to segregate with von Hippel-Lindau syndrome in two families (PMID: 12603429, 20447124). Experimental studies have shown that this missense change disrupts the normal function of VHL protein (PMID: 26973240, 11739384, 10823831). This suggests that the arginine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. This variant has been reported to be de novo in an individual affected with bilateral adrenal pheochromocytoma (PMID: 23327821). In addition, this variant has been reported to segregate with bilateral pheochromocytoma in one family (PMID: 23626751). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 82 of the VHL protein (p.Arg82Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. (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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Clinical presentation, genotype-phenotype correlations, and outcome of pancreatic neuroendocrine tumors in Von Hippel-Lindau syndrome. | Penitenti F | Endocrine | 2021 | PMID: 34036514 |
Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. | Ben Aim L | Journal of medical genetics | 2019 | PMID: 30877234 |
Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors. | Krauss T | Endocrine-related cancer | 2018 | PMID: 29748190 |
Clinical and Molecular Features of Renal and Pheochromocytoma/Paraganglioma Tumor Association Syndrome (RAPTAS): Case Series and Literature Review. | Casey RT | The Journal of clinical endocrinology and metabolism | 2017 | PMID: 28973655 |
Phosphorylation-dependent cleavage regulates von Hippel Lindau proteostasis and function. | German P | Oncogene | 2016 | PMID: 26973240 |
Mutations seen among patients with pheochromocytoma and paraganglioma at a referral center from India. | Pai R | Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | 2015 | PMID: 24977658 |
P.Arg82Leu von Hippel-Lindau (VHL) gene mutation among three members of a family with familial bilateral pheochromocytoma in India: molecular analysis and in silico characterization. | John AM | PloS one | 2013 | PMID: 23626751 |
Detection of large deletions in the VHL gene using a Real-Time PCR with SYBR Green. | Ebenazer A | Familial cancer | 2013 | PMID: 23397066 |
Bilateral pheochromocytomas in a child who had hemihypertrophy and alteration in the VHL gene. | Amini Z | Journal of pediatric endocrinology & metabolism : JPEM | 2013 | PMID: 23327821 |
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 |
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 |
A type 2B von Hippel-Lindau family masquerading as a metastatic sporadic renal cell carcinoma. | André T | BJU international | 2003 | PMID: 12603429 |
Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein. | Li Z | The Journal of biological chemistry | 2002 | PMID: 11739384 |
Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. | Cockman ME | The Journal of biological chemistry | 2000 | PMID: 10823831 |
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Text-mined citations for rs794726890 ...
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.