ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.208G>A (p.Glu70Lys)
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.208G>A (p.Glu70Lys)
Variation ID: 43598 Accession: VCV000043598.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10142055 (GRCh38) [ NCBI UCSC ] 3: 10183739 (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 8, 2016 Feb 28, 2024 Nov 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.208G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Glu70Lys missense NM_001354723.2:c.208G>A NP_001341652.1:p.Glu70Lys missense NM_198156.3:c.208G>A NP_937799.1:p.Glu70Lys missense NC_000003.12:g.10142055G>A NC_000003.11:g.10183739G>A NG_008212.3:g.5421G>A LRG_322:g.5421G>A LRG_322t1:c.208G>A LRG_322p1:p.Glu70Lys P40337:p.Glu70Lys - Protein change
- E70K
- Other names
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- Canonical SPDI
- NC_000003.12:10142054:G:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2023 | RCV000036540.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 9, 2017 | RCV000492137.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 8, 2023 | RCV001379599.6 |
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
(Apr 10, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697485.2
First in ClinVar: Mar 08, 2016 Last updated: Jun 03, 2023 |
Comment:
Variant summary: VHL c.208G>A (p.Glu70Lys) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the … (more)
Variant summary: VHL c.208G>A (p.Glu70Lys) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 229204 control chromosomes (gnomAD). c.208G>A has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (examples: Hes_2007 and Hwang_2014). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 01, 2016)
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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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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782417.1
First in ClinVar: Mar 08, 2016 Last updated: Mar 08, 2016 |
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Likely pathogenic
(Nov 01, 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: SCV004185990.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15611064]. This variant has been reported in multiple individuals with … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15611064]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25078357, 27439424, 36384467, 31087189]. (less)
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Pathogenic
(Nov 08, 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: SCV001577426.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 70 of the VHL protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 70 of the VHL protein (p.Glu70Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of von Hippel-Lindau syndrome (VHL) (PMID: 9829912, 17661816, 19270817, 19408298, 25078357, 25562111, 25715769, 27439424; Invitae). It is commonly reported in individuals of Korean ancestry (PMID: 25078357). ClinVar contains an entry for this variant (Variation ID: 43598). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 15611064). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: curation
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von Hippel-Lindau disease
Associated Phenotypes (From HPO):
(more...)
Affected status: unknown
Allele origin:
germline
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CIViC knowledgebase, Washington University School of Medicine
Accession: SCV001192829.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
Comment:
VHL E70K (c.208G>A) is Likely Pathogenic. E70K missense variant occurs at a very low allele frequency in the general population (0.00001489 allele frequency in ExAC, … (more)
VHL E70K (c.208G>A) is Likely Pathogenic. E70K missense variant occurs at a very low allele frequency in the general population (0.00001489 allele frequency in ExAC, 4.365e-6 allele frequency in gnomAD) and was previously identified in several unrelated individuals with VHL disease symptoms (see evidence statements). PM1 (6860); PM2 (per above); PP1 (5805); PP4 (5805;6742). (less)
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Likely pathogenic
(Oct 09, 2017)
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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: SCV000580979.5
First in ClinVar: Jul 01, 2017 Last updated: Nov 29, 2022 |
Comment:
The p.E70K variant (also known as c.208G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide … (more)
The p.E70K variant (also known as c.208G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 208. The glutamic acid at codon 70 is replaced by lysine, an amino acid with similar properties. Some studies have proposed this alteration as a Korean hotspot mutation that causes a phenotype consistent with VHL type 1 (Hwang S et al. J. Hum. Genet. 2014 Sep;59(9):488-93; Lee JS et al. BMC Med. Genet. 2016 Jul;17(1):48). It has been identified in many unrelated Korean families with histories of central nervous system and retinal hemangioblastomas (Olschwang S et al. Hum Mut. 1998;12:424; Hes FJ et al. Clin Genet. 2007;72:122; Cho HJ et al. J Korean Med Sci. 2009 Feb;24(1):77-83; Hwang S et al. J. Hum. Genet. 2014 Sep;59(9):488-93; Lee JS et al. BMC Med. Genet. 2016 Jul;17(1):48). It was also seen in a 74-year-old Korean patient with renal clear cell carcinoma and central nervous system hemangioblastomas, as well as a colorectal adenocarcinoma. This patient's two brothers, also presenting with renal cell carcinoma, were positive for the p.E70K alteration (Heo SJ et al. Cancer Res Treat. 2016 Jan;48(1):409-14). In addition, a functional study demonstrated that this alteration led to a modest reduction (20%) in the ability of the VHL protein to bind with the alpha subunit of the hypoxia-inducible transcription factor (HIF) and failure to degrade HIF-2 alpha (Miller F et al. J Biol Chemistry. 2005;280(9):7986). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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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: SCV000264671.1
First in ClinVar: Mar 08, 2016 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 2
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Pathogenic
(Apr 11, 2007)
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no assertion criteria provided
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060195.5
First in ClinVar: May 03, 2013 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 2
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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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Von Hipple-Lindau disease complicated with central retinal vein occlusion: a case report. | Chen X | BMC ophthalmology | 2022 | PMID: 36384467 |
The incidence of consecutive manifestations in Von Hippel-Lindau disease. | van der Horst-Schrivers ANA | Familial cancer | 2019 | PMID: 31087189 |
Clinical and molecular characteristics of East Asian patients with von Hippel-Lindau syndrome. | Wong M | Chinese journal of cancer | 2016 | PMID: 27527340 |
Genotype-phenotype analysis of von Hippel-Lindau syndrome in Korean families: HIF-α binding site missense mutations elevate age-specific risk for CNS hemangioblastoma. | Lee JS | BMC medical genetics | 2016 | PMID: 27439424 |
A Case of von Hippel-Lindau Disease with Colorectal Adenocarcinoma, Renal Cell Carcinoma and Hemangioblastomas. | Heo SJ | Cancer research and treatment | 2016 | PMID: 25715769 |
Clinical features of pancreatic involvement in von Hippel-Lindau disease: a retrospective study of 55 cases in a single center. | Park TY | Scandinavian journal of gastroenterology | 2015 | PMID: 25562111 |
Calculating optimal surveillance for detection of von Hippel-Lindau-related manifestations. | Kruizinga RC | Endocrine-related cancer | 2013 | PMID: 24132471 |
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 |
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 |
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 |
Inactivation of VHL by tumorigenic mutations that disrupt dynamic coupling of the pVHL.hypoxia-inducible transcription factor-1alpha complex. | Miller F | The Journal of biological chemistry | 2005 | PMID: 15611064 |
Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. | Olschwang S | Human mutation | 1998 | PMID: 9829912 |
https://civicdb.org/links/assertions/14 | - | - | - | - |
https://civicdb.org/links/evidence/5273 | - | - | - | - |
https://civicdb.org/links/evidence/5780 | - | - | - | - |
https://civicdb.org/links/evidence/5805 | - | - | - | - |
https://civicdb.org/links/evidence/6503 | - | - | - | - |
https://civicdb.org/links/evidence/6742 | - | - | - | - |
https://civicdb.org/links/evidence/6860 | - | - | - | - |
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Text-mined citations for rs5030802 ...
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.