ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.473T>C (p.Leu158Pro)
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.473T>C (p.Leu158Pro)
Variation ID: 182980 Accession: VCV000182980.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10149796 (GRCh38) [ NCBI UCSC ] 3: 10191480 (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 May 1, 2024 Jul 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.473T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Leu158Pro missense NM_001354723.2:c.*27T>C 3 prime UTR NM_198156.3:c.350T>C NP_937799.1:p.Leu117Pro missense NC_000003.12:g.10149796T>C NC_000003.11:g.10191480T>C NG_008212.3:g.13162T>C NG_046756.1:g.7558T>C LRG_322:g.13162T>C LRG_322t1:c.473T>C LRG_322p1:p.Leu158Pro P40337:p.Leu158Pro - Protein change
- L158P, L117P
- Other names
- p.L158P:CTG>CCG
- Canonical SPDI
- NC_000003.12:10149795: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
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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 |
818 | 1978 | |
LOC107303340 | - | - | - | GRCh38 | - | 1112 |
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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Jun 17, 2021 | RCV000161088.4 | |
Pathogenic (2) |
criteria provided, single submitter
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Feb 4, 2016 | RCV000208846.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2023 | RCV000492547.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 17, 2023 | RCV001072084.5 |
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
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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
(Feb 04, 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: SCV000697519.1
First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016 |
Comment:
Variant summary: The c.473T>C variant affects a conserved nucleotide, resulting in amino acid change from Leu to Pro. 4/4 in-silico tools predict damaging outcome for … (more)
Variant summary: The c.473T>C variant affects a conserved nucleotide, resulting in amino acid change from Leu to Pro. 4/4 in-silico tools predict damaging outcome for this variant. This variant has been reported in at least 8 VHL patients and not found in 120292 control chromosomes. In addition, one clinical laboratory classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. (less)
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Pathogenic
(Mar 29, 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: SCV000580975.7
First in ClinVar: Jul 01, 2017 Last updated: May 01, 2024 |
Comment:
The p.L158P pathogenic mutation (also known as c.473T>C), located in coding exon 3 of the VHL gene, results from a T to C substitution at … (more)
The p.L158P pathogenic mutation (also known as c.473T>C), located in coding exon 3 of the VHL gene, results from a T to C substitution at nucleotide position 473. The leucine at codon 158 is replaced by proline, an amino acid with similar properties. This variant has been reported in several families with VHL (Whaley JM et al. Am. J. Hum. Genet. 1994 Dec;55(6):1092-102; Olschwang S et al. Hum Mutat. 1998;12(6):424-30; Ambry internal data). Of note, this variant may be referred to as c.686T>C in older literature.This alteration has been shown to disrupt the ability of the chaperone complex elongin-BC to bind to the VHL protein which leads to improper protein folding (McClellan AJ et al. Cell. 2005 Jun 3;121(5):739-48). One in vitro functional study showed that this variant produced an unstable VHL protein. The authors also show that a p.L158P mutant cell line displayed the same disorganized, fibroblastic morphology as seen in other VHL mutants, and classified this variant as a type 1 VHL mutation (Bangiyeva V et al.. BMC Cancer. 2009 Jul 14;9:229). 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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Pathogenic
(Jun 17, 2021)
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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: SCV000211823.6
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
Published functional studies demonstrate a damaging effect: reduced HIF1-alpha ubiquinitation, disrupted stability, impaired ability to bind to elongin B and C, and disrupted folding of … (more)
Published functional studies demonstrate a damaging effect: reduced HIF1-alpha ubiquinitation, disrupted stability, impaired ability to bind to elongin B and C, and disrupted folding of the VHL protein (Feldman 1999, Kamura 2000, McClellan 2005, Bangiyeva 2009); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 686T>C, Leu229Pro; This variant is associated with the following publications: (PMID: 8956040, 10635329, 11331612, 7977367, 6582782, 12202531, 15300849, 17661816, 9829912, 10973499, 15935760, 14987375, 27535533, 19955664, 19602254) (less)
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Pathogenic
(Jul 17, 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: SCV001237427.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This variant disrupts the p.Leu158 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10761708, 14722919, … (more)
This variant disrupts the p.Leu158 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10761708, 14722919, 19574279, 28052007). 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. Experimental studies have shown that this missense change affects VHL function (PMID: 7553625, 11331613, 19602254, 28775317). 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: 182980). This variant is also known as 686T>C (Leu229Pro). This missense change has been observed in individuals with von Hippel-Lindau syndrome and sporadic renal cell carcinoma (PMID: 1056348, 7728151, 7977367, 10408776, 12202531, 15300849, 17661816, 20351605, 23070752, 25867206; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 158 of the VHL protein (p.Leu158Pro). (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: SCV000264754.1
First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016 |
Number of individuals with the variant: 11
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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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Interaction between von Hippel-Lindau Protein and Fatty Acid Synthase Modulates Hypoxia Target Gene Expression. | Sun W | Scientific reports | 2017 | PMID: 28775317 |
VHL missense mutations in the p53 binding domain show different effects on p53 signaling and HIFα degradation in clear cell renal cell carcinoma. | Razafinjatovo CF | Oncotarget | 2017 | PMID: 28052007 |
Characterization of endolymphatic sac tumors and von Hippel-Lindau disease in the International Endolymphatic Sac Tumor Registry. | Bausch B | Head & neck | 2016 | PMID: 25867206 |
Surgical resection of endolymphatic sac tumors in von Hippel-Lindau disease: findings, results, and indications. | Kim HJ | The Laryngoscope | 2013 | PMID: 23070752 |
Endolymphatic sac tumors in von Hippel-Lindau disease: report of three cases. | Codreanu CM | Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology | 2010 | PMID: 20351605 |
Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes. | Bangiyeva V | BMC cancer | 2009 | PMID: 19602254 |
Germline VHL gene mutations in Hungarian families with von Hippel-Lindau disease and patients with apparently sporadic unilateral pheochromocytomas. | Gergics P | European journal of endocrinology | 2009 | PMID: 19574279 |
Frequency of Von Hippel-Lindau germline mutations in classic and non-classic Von Hippel-Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe amplification. | Hes FJ | Clinical genetics | 2007 | PMID: 17661816 |
Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions. | Gallou C | Human mutation | 2004 | PMID: 15300849 |
Genetic characterization and structural analysis of VHL Spanish families to define genotype-phenotype correlations. | Ruiz-Llorente S | Human mutation | 2004 | PMID: 14722919 |
Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study. | Dollfus H | Investigative ophthalmology & visual science | 2002 | PMID: 12202531 |
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 |
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 |
Detection of a novel germline mutation in the von Hippel-Lindau tumour-suppressor gene by fluorescence-labelled base excision sequence scanning (F-BESS). | Brieger J | Clinical genetics | 1999 | PMID: 10563480 |
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 |
Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. | Olschwang S | Human mutation | 1998 | PMID: 9829912 |
Detection of germline mutations in the von Hippel-Lindau disease gene by the primer specified restriction map modification method. | Kishida T | Journal of medical genetics | 1995 | PMID: 8825919 |
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 |
Germ-line mutations in the von Hippel-Lindau tumor-suppressor gene are similar to somatic von Hippel-Lindau aberrations in sporadic renal cell carcinoma. | Whaley JM | American journal of human genetics | 1994 | PMID: 7977367 |
Effect of sugar analogues on growth, sugar utilization, and acid production by Streptococcus mutans. | Schachtele DF | Journal of dental research | 1975 | PMID: 1056348 |
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Text-mined citations for rs121913346 ...
HelpRecord last updated May 01, 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.