ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.562C>G (p.Leu188Val)
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
-
NM_000551.4(VHL):c.562C>G (p.Leu188Val)
Variation ID: 2225 Accession: VCV000002225.46
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p25.3 3: 10149885 (GRCh38) [ NCBI UCSC ] 3: 10191569 (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 8, 2016 May 12, 2024 Feb 22, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000551.4:c.562C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Leu188Val missense NM_001354723.2:c.*116C>G 3 prime UTR NM_198156.3:c.439C>G NP_937799.1:p.Leu147Val missense NC_000003.12:g.10149885C>G NC_000003.11:g.10191569C>G NG_008212.3:g.13251C>G NG_046756.1:g.7647C>G LRG_322:g.13251C>G LRG_322t1:c.562C>G LRG_322p1:p.Leu188Val P40337:p.Leu188Val - Protein change
- L188V, L147V
- Other names
- -
- Canonical SPDI
- NC_000003.12:10149884:C:G
-
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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
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 |
817 | 1975 | |
LOC107303340 | - | - | - | GRCh38 | - | 1111 |
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/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Feb 22, 2024 | RCV000002311.23 | |
Pathogenic (1) |
no assertion criteria provided
|
Feb 15, 2003 | RCV000002313.7 | |
Pathogenic (2) |
criteria provided, single submitter
|
Apr 23, 2023 | RCV000002312.8 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 26, 2023 | RCV000210199.12 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 16, 2023 | RCV000480890.22 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV000627743.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV003330076.1 |
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
(Nov 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266137.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
Number of individuals with the variant: 1
Clinical Features:
kidney cancer (present)
Age: 40-49 years
|
|
Pathogenic
(Dec 15, 2020)
|
criteria provided, single submitter
Method: research
|
Von Hippel-Lindau syndrome
Affected status: no
Allele origin:
germline
|
Department of Pediatrics, Memorial Sloan Kettering Cancer Center
Accession: SCV001478193.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
|
|
Pathogenic
(Apr 01, 2021)
|
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: SCV001572439.1
First in ClinVar: Apr 30, 2021 Last updated: Apr 30, 2021 |
Comment:
Variant summary: VHL c.562C>G (p.Leu188Val) results in a conservative amino acid change located in the alpha domain (IPR024048) of the encoded protein sequence. Four of … (more)
Variant summary: VHL c.562C>G (p.Leu188Val) results in a conservative amino acid change located in the alpha domain (IPR024048) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251424 control chromosomes (gnomAD). c.562C>G has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (example: Neumann_1995, Glavac_1996). Individuals from two of these families also had C-cell tumor and extra adrenal pheochromocytoma. The variant also reported to segregate in a family where most of the affected individuals had only pheochromocytoma (Ritter_1996). In functional studies, the variant was able to direct polyubiquitination of transcription factor HIF (hypoxia-inducible factor) but was partially defective to promoting extracellular fibronectin matrix formation (Hoffman_2001). Kurban et al report that in matrigel assays, the renal carcinoma cells expressing the variant were shown to be highly invasive and in nude mouse xenograft assays they were capable of generating highly vascularized tumors (Kurban_2006). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic (n=6) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Likely pathogenic
(Aug 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568596.8
First in ClinVar: Apr 29, 2017 Last updated: Aug 24, 2023 |
Comment:
Observed in the heterozygous state in multiple adult individuals without VHL-related tumors tested at GeneDx and in the literature, suggesting this variant may be associated … (more)
Observed in the heterozygous state in multiple adult individuals without VHL-related tumors tested at GeneDx and in the literature, suggesting this variant may be associated with reduced penetrance (Huang et al., 2018; Panou et al., 2018; eMERGE consortium et al., 2019; Kuhlman et al., 2021; Savatt et al., 2022); Published functional studies demonstrate retained ability to ubiquitinate and degrade hypoxia-inducible factor (HIF)-1 as well as downregulate HIF-1 target genes, normal to reduced protein stability, and retained or reduced protein binding, but also show defective fibronectin extracellular matrix assembly as well as impaired interaction with mitochondrial proteins (Ohh et al., 2000; Clifford et al., 2001; Hoffman et al., 2001; Gunaratnam et al., 2003; Rathmell et al., 2004; Esteban et al., 2006; Kurban et al., 2006; Hacker et al., 2008; Kurban et al., 2008; Bangiyeva et al., 2009; Knauth et al., 2009; Heir et al., 2016; Tedesco et al., 2019; Li et al., 2022); Co-observed with a second VHL variant in individuals with recessively-inherited congenital polycythemia (Pastore et al., 2003; Bento et al., 2005; Lorenzo et al., 2013; Gangat et al., 2022); however, additional evidence is needed to establish whether there is a relationship between this variant and autosomal recessive disease; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as Leu259Val; This variant is associated with the following publications: (PMID: 12097293, 11331613, 23772956, 7987306, 8772572, 11331612, 19030229, 16585181, 8634692, 15177666, 12000816, 19228690, 7563486, 22393103, 11409863, 27517496, 30105105, 30113886, 19602254, 16452184, 18567581, 15642680, 18836774, 19906784, 25371412, 28620007, 27114602, 24969085, 12844285, 28235946, 28945216, 28503092, 8707293, 10878807, 8956040, 29478617, 12944410, 26846855, 15574766, 17898043, 29790589, 29625052, 30890701, 9829911, 31447099, 31980715, 32869749, 34308366, 34720947, 35205407, 34628056, 29748190, 17700531, 35760869, 35668420, 33720516, 35142155, 12414898) (less)
|
|
Pathogenic
(Apr 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020861.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jan 31, 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
|
Invitae
Accession: SCV000262041.12
First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 188 of the VHL protein (p.Leu188Val). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 188 of the VHL protein (p.Leu188Val). This variant is present in population databases (rs5030824, gnomAD 0.006%). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7563486, 7987306, 8772572, 12844285, 15642680, 23772956). It has also been observed to segregate with disease in related individuals. This variant is also known as Leu259Val, Leu229Val, and C775G. ClinVar contains an entry for this variant (Variation ID: 2225). 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%. Experimental studies have shown that this missense change affects VHL function (PMID: 11331612, 16452184, 18567581, 19228690, 23772956). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004822001.1
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)
|
Comment:
The c.562C>G (p.Leu188Val) variant in the VHL gene has been reported in patients with Von Hippel-Lindau syndrome [PMID 12414898, 12000816]. The variant was originally detected … (more)
The c.562C>G (p.Leu188Val) variant in the VHL gene has been reported in patients with Von Hippel-Lindau syndrome [PMID 12414898, 12000816]. The variant was originally detected in two families diagnosed with mutiple endocrine neoplasia type IIA but without a RET pathogenic variant [PMID 7563486]. This variant was further detected and characterized as a pathogenic variant in patients with VHL type IIC, a disorder characterized with a risk for pheochromocytoma only [PMID 12414898, 12000816]. This variant was detected in 1/271 patients presenting with non syndromic pheochromocytoma [PMID 12000816]. It was also detected and showed to co- segregate with pheochromocytoma in a family with 6 affected individuals [PMID 12414898]. The variant was found in cis configuration with a p.Pro81Ser variant; however the p.Pro81Ser variant is now classified as likely benign and thus not thought to affect the phenotype of these reported patients. This p.Leu188Val was also reported in two siblings with congenital polycythaemia [PMID 23772956]. In vitro assays showed that this variant affects the extra cellular matrix assembly, which correlated with tumor angiogenesis [PMID 16452184]. The amino acid position 188 of the VHL protein is a hot spot for pathogenic variants causing Von Hippel-Lindau syndrome: additional variants affecting the same amino acid at position 188 (p.Leu188Arg, p.Leu188Gln and p.Leu188Pro) have been reported. This variant was observed in two European (Non Finnish) at the heterozygous state in the ExAC database (http://exac.broadinstitute.org/variant/3-10191569-C-G). Leucine at amino acid position 188 of the VHL protein is highly conserved in mammals and while not clinically validated, computer-based algorithms predict this p.Leu188Val change to be deleterious. This variant is thus classified as pathogenic. (less)
Number of individuals with the variant: 10
|
|
Likely Pathogenic
(Feb 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731611.3
First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024 |
Comment:
The p.Leu188Val variant in VHL (also described as p.Leu259Val in the literature) has been reported in the heterozygous state in 6 individuals with von Hippel-Lindau … (more)
The p.Leu188Val variant in VHL (also described as p.Leu259Val in the literature) has been reported in the heterozygous state in 6 individuals with von Hippel-Lindau syndrome type 2C and segregated with disease in at least 12 affected relatives from 2 families (Neumann 1995 PMID: 7563486, Ritter 1996 PMID: 8772572, Zbar 1996 PMID: 8956040, Neumann 2002 PMID: 12000816, Weirich 2002 PMID: 12414898). This variant has also been reported in the compound heterozygous state in 3 individuals with congenital polycythemia (Pastore 2003 PMID: 12844285, Bento 2005 PMID: 15642680). However, it has also been identified in 0.003% (39/1180038) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). Furthermore, it has been identified in multiple adults with no known VHL-related tumors, suggesting that it may be associated with reduced penetrance (Savatt 2022 PMID: 35668420, Ambry Genetics personal communication). This variant has been reported in ClinVar (Variation ID 2225). In vitro functional studies provide some evidence that the p.Leu188Val variant may impact protein function (Hoffman 2001 PMID: 11331612, Kurban 2006 PMID: 16452184, Knauth 2009 PMID: 19228690). Computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant von Hippel-Lindau syndrome type 2C, however its penetrance may be reduced. ACMG/AMP codes applied: PS4_Moderate, PP1_Strong, PS3_Supporting, PP3. (less)
|
|
Likely pathogenic
(Feb 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004933645.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7563486, 8772572, 19906784, 34628056].
|
|
Pathogenic
(Apr 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002563751.11
First in ClinVar: Aug 23, 2022 Last updated: May 12, 2024 |
Comment:
VHL: PP1:Strong, PS4, PM1, PS3:Supporting
Number of individuals with the variant: 1
|
|
Pathogenic
(May 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000840080.1
First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018 |
Comment:
The c.562C>G (p.Leu188Val) variant has been reported in patients with Von Hippel-Lindau syndrome [PMID 12414898, 12000816]. The variant was originally detected in two families diagnosed … (more)
The c.562C>G (p.Leu188Val) variant has been reported in patients with Von Hippel-Lindau syndrome [PMID 12414898, 12000816]. The variant was originally detected in two families diagnosed with mutiple endocrine neoplasia type IIA but without a RET pathogenic variant [PMID 7563486]. This variant was further detected and characterized as a pathogenic variant in patients with VHL type IIC, a disorder characterized with a risk for pheochromocytoma only [PMID 12414898, 12000816]. This variant was detected in 1/271 patients presenting with non syndromic pheochromocytoma [PMID 12000816]. It was also detected and showed to co- segregate with pheochromocytoma in a family with 6 affected individuals [PMID 12414898]. The variant was found in cis configuration with a p.Pro81Ser variant; however the p.Pro81Ser variant is now classified as likely benign and thus not thought to affect the phenotype of these reported patients. This p.Leu188Val was also reported in two siblings with congenital polycythaemia [PMID 23772956]. In vitro assays showed that this variant affects the extra cellular matrix assembly, which correlated with tumor angiogenesis [PMID 16452184]. The amino acid position 188 of the VHL protein is a hot spot for pathogenic variants causing Von Hippel-Lindau syndrome: additional variants affecting the same amino acid at position 188 (p.Leu188Arg, p.Leu188Gln and p.Leu188Pro) have been reported. This variant was observed in two European (Non Finnish) at the heterozygous state in the ExAC database (http://exac.broadinstitute.org/variant/3-10191569-C-G). Leucine at amino acid position 188 of the VHL protein is highly conserved in mammals and while not clinically validated, computer-based algorithms predict this p.Leu188Val change to be deleterious. This variant is thus classified as pathogenic. (less)
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: not provided
|
Au-Kline syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Accession: SCV004037185.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Clinical Features:
Global developmental delay (present) , Tachycardia (present) , Tachypnea (present) , Autosomal dominant inheritance (present)
|
|
Pathogenic
(Apr 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Chuvash polycythemia
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004208786.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Likely pathogenic
(Dec 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000664527.7
First in ClinVar: Mar 20, 2016 Last updated: May 01, 2024 |
Comment:
The p.L188V variant (also known as c.562C>G), located in coding exon 3 of the VHL gene, results from a C to G substitution at nucleotide … (more)
The p.L188V variant (also known as c.562C>G), located in coding exon 3 of the VHL gene, results from a C to G substitution at nucleotide position 562. The leucine at codon 188 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in several individuals and families with VHL or VHL related tumors (Ritter MM et al. J. Clin. Endocrinol. Metab. 1996 Mar;81(3):1035-7; Neumann HP et al. JAMA. 1995 Oct;274(14):1149-51; Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3(8):1303-8; Weirich G et al. J Clin Endocrinol Metab, 2002 Nov;87:5241-6) and in conjunction with a VHL mutation in multiple individuals affected with autosomal recessive polycythemia (Bento MC et al. Haematologica. 2005 Jan;90(1):128-9; Lorenzo FR et al. Br. J. Haematol. 2013 Sep;162(6):851-3; Pastore Y et al. Am J Hum Genet, 2003 Aug;73:412-9). Functional studies demonstrate that this variant is characteristic of VHL type 2C alterations in that it maintains the ability to ubiquitinate and downregulate key targets such as HIF2a (Hoffman MA et al. Hum. Mol. Genet., 2001 May;10:1019-27; Hacker KE et al. PLoS ONE, 2008 Nov;3:e3801), and is deficient at extracellular matrix formation (Kurban G et al. Cancer Res., 2006 Feb;66:1313-9). Further studies which injected human RCC cells containing this variant into nude mice showed the formation of highly vascularized, invasive tumors in contrast to those containing wild type VHL that formed no tumors (Kurban G et al. Cancer Res., 2006 Feb;66:1313-9). This alteration has been identified in numerous individuals that do not have a diagnosis of VHL, or any VHL associated tumors (Ambry internal data) suggesting this variant may be associated with significantly reduced penetrance. 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 majority of available evidence to date, p.L188V is likely to be a low penetrance pathogenic variant and may not be associated with classic von Hippel Lindau disease or associated tumors. Clinical correlation is advised. (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: SCV000264772.1
First in ClinVar: Mar 08, 2016 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 4
|
|
Pathogenic
(Feb 15, 2003)
|
no assertion criteria provided
Method: literature only
|
VON HIPPEL-LINDAU SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022469.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2020 |
Comment on evidence:
In a family with von Hippel-Lindau syndrome (VHLS; 193300), Neumann et al. (1995) identified a leu188-to-val (L188V) mutation in the VHL gene. Nine patients had … (more)
In a family with von Hippel-Lindau syndrome (VHLS; 193300), Neumann et al. (1995) identified a leu188-to-val (L188V) mutation in the VHL gene. Nine patients had pheochromocytoma without renal carcinoma (Zbar et al., 1996). In 6 members of the same German family identified by Neumann et al. (1995) with von Hippel-Lindau syndrome type 2C, Weirich et al. (2002) found a P81S mutation in the VHL gene (608537.0020), which cosegregated with the L188V mutation. Weirich et al. (2002) discussed the possible impact of these mutations on protein function and phenotype. In 2 unrelated white American children, a 15-year-old male and a 13-year-old female, who presented at 5 years of age with familial erythrocytosis (ECYT2; 263400), Pastore et al. (2003) identified a 562C-G transversion in the VHL gene, resulting in the L188V mutation. In both patients the mutation occurred in compound heterozygous state with the common R200W mutation (608537.0019). Neumann et al. (2002) identified the L188V mutation in the germline of a patient with sporadic pheochromocytoma (171300). The mutation was not identified in 600 control chromosomes. (less)
|
|
Pathogenic
(Feb 15, 2003)
|
no assertion criteria provided
Method: literature only
|
ERYTHROCYTOSIS, FAMILIAL, 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022470.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2020 |
Comment on evidence:
In a family with von Hippel-Lindau syndrome (VHLS; 193300), Neumann et al. (1995) identified a leu188-to-val (L188V) mutation in the VHL gene. Nine patients had … (more)
In a family with von Hippel-Lindau syndrome (VHLS; 193300), Neumann et al. (1995) identified a leu188-to-val (L188V) mutation in the VHL gene. Nine patients had pheochromocytoma without renal carcinoma (Zbar et al., 1996). In 6 members of the same German family identified by Neumann et al. (1995) with von Hippel-Lindau syndrome type 2C, Weirich et al. (2002) found a P81S mutation in the VHL gene (608537.0020), which cosegregated with the L188V mutation. Weirich et al. (2002) discussed the possible impact of these mutations on protein function and phenotype. In 2 unrelated white American children, a 15-year-old male and a 13-year-old female, who presented at 5 years of age with familial erythrocytosis (ECYT2; 263400), Pastore et al. (2003) identified a 562C-G transversion in the VHL gene, resulting in the L188V mutation. In both patients the mutation occurred in compound heterozygous state with the common R200W mutation (608537.0019). Neumann et al. (2002) identified the L188V mutation in the germline of a patient with sporadic pheochromocytoma (171300). The mutation was not identified in 600 control chromosomes. (less)
|
|
Pathogenic
(Feb 15, 2003)
|
no assertion criteria provided
Method: literature only
|
PHEOCHROMOCYTOMA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022471.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2020 |
Comment on evidence:
In a family with von Hippel-Lindau syndrome (VHLS; 193300), Neumann et al. (1995) identified a leu188-to-val (L188V) mutation in the VHL gene. Nine patients had … (more)
In a family with von Hippel-Lindau syndrome (VHLS; 193300), Neumann et al. (1995) identified a leu188-to-val (L188V) mutation in the VHL gene. Nine patients had pheochromocytoma without renal carcinoma (Zbar et al., 1996). In 6 members of the same German family identified by Neumann et al. (1995) with von Hippel-Lindau syndrome type 2C, Weirich et al. (2002) found a P81S mutation in the VHL gene (608537.0020), which cosegregated with the L188V mutation. Weirich et al. (2002) discussed the possible impact of these mutations on protein function and phenotype. In 2 unrelated white American children, a 15-year-old male and a 13-year-old female, who presented at 5 years of age with familial erythrocytosis (ECYT2; 263400), Pastore et al. (2003) identified a 562C-G transversion in the VHL gene, resulting in the L188V mutation. In both patients the mutation occurred in compound heterozygous state with the common R200W mutation (608537.0019). Neumann et al. (2002) identified the L188V mutation in the germline of a patient with sporadic pheochromocytoma (171300). The mutation was not identified in 600 control chromosomes. (less)
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Observational study of population genomic screening for variants associated with endocrine tumor syndromes in a large, healthcare-based cohort. | Savatt JM | BMC medicine | 2022 | PMID: 35668420 |
Pathogenicity of VHL variants in families with non-syndromic von Hippel-Lindau phenotypes: An integrated evaluation of germline and somatic genomic results. | Rana HQ | European journal of medical genetics | 2021 | PMID: 34628056 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
Novel compound VHL heterozygosity (VHL T124A/L188V) associated with congenital polycythaemia. | Lorenzo FR | British journal of haematology | 2013 | PMID: 23772956 |
Pathogenicity of DNA variants and double mutations in multiple endocrine neoplasia type 2 and von Hippel-Lindau syndrome. | Erlic Z | The Journal of clinical endocrinology and metabolism | 2010 | PMID: 19906784 |
Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes. | Bangiyeva V | BMC cancer | 2009 | PMID: 19602254 |
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 |
VHL type 2B mutations retain VBC complex form and function. | Hacker KE | PloS one | 2008 | PMID: 19030229 |
Computational detection of deleterious SNPs and their effect on sequence and structural level of the VHL gene. | Rajasekaran R | Mammalian genome : official journal of the International Mammalian Genome Society | 2008 | PMID: 18836774 |
Inadequate activation of the GTPase RhoA contributes to the lack of fibronectin matrix assembly in von Hippel-Lindau protein-defective renal cancer cells. | Feijóo-Cuaresma M | The Journal of biological chemistry | 2008 | PMID: 18567581 |
Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. | Kurban G | Cancer research | 2006 | PMID: 16452184 |
Congenital polycythemia with homozygous and heterozygous mutations of von Hippel-Lindau gene: five new Caucasian patients. | Bento MC | Haematologica | 2005 | PMID: 15642680 |
Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. | Pastore Y | American journal of human genetics | 2003 | PMID: 12844285 |
Mutations in the VHL gene in sporadic apparently congenital polycythemia. | Pastore YD | Blood | 2003 | PMID: 12393546 |
VHL2C phenotype in a German von Hippel-Lindau family with concurrent VHL germline mutations P81S and L188V. | Weirich G | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 12414898 |
Germ-line mutations in nonsyndromic pheochromocytoma. | Neumann HP | The New England journal of medicine | 2002 | PMID: 12000816 |
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 |
Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. | Stolle C | Human mutation | 1998 | PMID: 9829911 |
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 |
Isolated familial pheochromocytoma as a variant of von Hippel-Lindau disease. | Ritter MM | The Journal of clinical endocrinology and metabolism | 1996 | PMID: 8772572 |
Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe. | Glavac D | Human genetics | 1996 | PMID: 8707293 |
Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II. | Neumann HP | JAMA | 1995 | PMID: 7563486 |
Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. | Crossey PA | Human molecular genetics | 1994 | PMID: 7987306 |
click to load more click to collapse |
Text-mined citations for rs5030824 ...
HelpRecord last updated May 12, 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.