ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.233A>G (p.Asn78Ser)
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.233A>G (p.Asn78Ser)
Variation ID: 93326 Accession: VCV000093326.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 10142080 (GRCh38) [ NCBI UCSC ] 3: 10183764 (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 Feb 28, 2024 Nov 3, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.233A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Asn78Ser missense NM_001354723.2:c.233A>G NP_001341652.1:p.Asn78Ser missense NM_198156.3:c.233A>G NP_937799.1:p.Asn78Ser missense NC_000003.12:g.10142080A>G NC_000003.11:g.10183764A>G NG_008212.3:g.5446A>G LRG_322:g.5446A>G LRG_322t1:c.233A>G LRG_322p1:p.Asn78Ser P40337:p.Asn78Ser - Protein change
- N78S
- Other names
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- Canonical SPDI
- NC_000003.12:10142079:A:G
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Oct 28, 2020 | RCV000079207.20 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 13, 2022 | RCV000254892.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 2, 2021 | RCV000492165.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 3, 2022 | RCV001034687.13 |
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
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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
(Oct 19, 2017)
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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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Counsyl
Accession: SCV000785647.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Pathogenic
(Nov 06, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000805330.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
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Pathogenic
(Sep 02, 2021)
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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: SCV000580971.5
First in ClinVar: Jul 01, 2017 Last updated: Nov 29, 2022 |
Comment:
The p.N78S pathogenic mutation (also known as c.233A>G) is located in coding exon 1 of the VHL gene and results from an A to G … (more)
The p.N78S pathogenic mutation (also known as c.233A>G) is located in coding exon 1 of the VHL gene and results from an A to G substitution at nucleotide position 233. The asparagine at codon 78 is replaced by serine, an amino acid with highly similar properties. This mutation has been reported in multiple individuals and families with VHL and has been shown to co-segregate with disease (Chen et al. Hum Mut. 1995; 5(1): 66-75; Zbar et al. Hum Mut. 1996 8:348-357; Cybulski et al. J Med Genet. 2002 Jul;39(7):E38; Zhang et al. J Cancer Res Clin Oncol. 2008 Nov;134(11):1211-8; Siu et al. Chin Med J (Engl). 2011 Jan;124(2):237-41; Lee JS et al. BMC Med. Genet. 2016 07;17(1):48; Cingoz S et al. Fam Cancer 2013 Mar;12(1):111-7; Lin G et al. Exp Ther Med 2020 Aug;20(2):1237-1244; Qi XP et al. Mol Med Rep 2013 Sep;8(3):799-805). In one study, the p.N78S mutation, a type1 VHL protein mutant, was expressed in VHL-negative renal cell carcinoma cell lines. The authors concluded that VHL has both HIF-á dependent and HIF-á independent functions in regulating tight junctions and cell morphology that likely impact the clinical phenotypes seen in VHL disease (Bangiyeva et al. BMC Cancer 2009. Jul 14;9:229). Of note, this alteration is also referred to as 446A>G (Asn149Ser) in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 03, 2022)
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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: SCV000626871.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This variant is also known as N149S. This missense change has been observed in individual(s) with von Hippel‚ÄìLindau disease (PMID: 7728151, 8956040, 12114495, 15109448, 15300849, … (more)
This variant is also known as N149S. This missense change has been observed in individual(s) with von Hippel–Lindau disease (PMID: 7728151, 8956040, 12114495, 15109448, 15300849, 19464396, 23842656). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 78 of the VHL protein (p.Asn78Ser). ClinVar contains an entry for this variant (Variation ID: 93326). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 19602254, 21454469). 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. (less)
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Pathogenic
(May 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000111077.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 5
Sex: mixed
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Pathogenic
(Oct 28, 2020)
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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: SCV001442590.1
First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020 |
Comment:
Variant summary: VHL c.233A>G (p.Asn78Ser) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta domain (IPR024053) of the … (more)
Variant summary: VHL c.233A>G (p.Asn78Ser) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta domain (IPR024053) 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 230680 control chromosomes (gnomAD). c.233A>G has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome and has been shown to co-segregate with disease in different families (e.g. Zbar_1996, Cybulski_2002, Dollfus_2002, Huang_2004). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant impairs protein function and stability and results in compromised tight junction formation, disorganized cell morphology and increased HIF (hypoxia-inducible factor) activation (e.g. Bangiyeva_2009, Bond_2011). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 13, 2022)
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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: SCV000322000.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: an unstable protein resulting in up-regulation of HIF-2a and Glut-1, down-regulation of P27, and the disruption of pVHL … (more)
Published functional studies demonstrate a damaging effect: an unstable protein resulting in up-regulation of HIF-2a and Glut-1, down-regulation of P27, and the disruption of pVHL and hVDU1 interactions in vitro (Li et al., 2002; Bangiyeva et al., 2009; Rechsteiner et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 446A>G; This variant is associated with the following publications: (PMID: 8730290, 16775032, 8707293, 19602254, 18836774, 23757202, 8634692, 7553625, 15300849, 17661816, 11409863, 12202531, 7591282, 10567493, 17024664, 14767899, 21362373, 9452106, 21454469, 11739384, 21715564, 10408776, 7728151, 25563310, 23842656, 27530247, 27439424, 26984080, 27527340, 12114495, 15109448, 30338240, 30787465, 8956040, 33720516, 18446368, 20233476, 28559085, 32742360) (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: SCV000264678.1
First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016 |
Number of individuals with the variant: 5
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Pathogenic
(Jul 10, 2019)
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no assertion criteria provided
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
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Clinical Genomics Labs, University Health Network
Accession: SCV001950147.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Genotype-phenotype correlations in Chinese von Hippel-Lindau disease patients. | Peng S | Oncotarget | 2017 | PMID: 28388566 |
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 |
E2-EPF UCP regulates stability and functions of missense mutant pVHL via ubiquitin mediated proteolysis. | Park KS | BMC cancer | 2015 | PMID: 26503325 |
p.N78S and p.R161Q germline mutations of the VHL gene are present in von Hippel-Lindau syndrome in two pedigrees. | Qi XP | Molecular medicine reports | 2013 | PMID: 23842656 |
VHL gene mutations and their effects on hypoxia inducible factor HIFα: identification of potential driver and passenger mutations. | Rechsteiner MP | Cancer research | 2011 | PMID: 21715564 |
Dysregulation of the HIF pathway due to VHL mutation causing severe erythrocytosis and pulmonary arterial hypertension. | Bond J | Blood | 2011 | PMID: 21454469 |
Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes. | Bangiyeva V | BMC cancer | 2009 | PMID: 19602254 |
Germline mutations in the von Hippel-Lindau gene in Italian patients. | Ciotti P | European journal of medical genetics | 2009 | PMID: 19464396 |
Formation of primary cilia in the renal epithelium is regulated by the von Hippel-Lindau tumor suppressor protein. | Esteban MA | Journal of the American Society of Nephrology : JASN | 2006 | PMID: 16775032 |
Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions. | Gallou C | Human mutation | 2004 | PMID: 15300849 |
Genetic study of a large Chinese kindred with von Hippel-Lindau disease. | Huang YR | Chinese medical journal | 2004 | PMID: 15109448 |
Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. | Hergovich A | Nature cell biology | 2003 | PMID: 12510195 |
Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study. | Dollfus H | Investigative ophthalmology & visual science | 2002 | PMID: 12202531 |
Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. | Cybulski C | Journal of medical genetics | 2002 | PMID: 12114495 |
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 |
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 |
Reconsideration of biallelic inactivation of the VHL tumour suppressor gene in hemangioblastomas of the central nervous system. | Gläsker S | Journal of neurology, neurosurgery, and psychiatry | 2001 | PMID: 11309459 |
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 mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. | Zbar B | Human mutation | 1996 | PMID: 8956040 |
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 |
Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. | Chen F | Human mutation | 1995 | PMID: 7728151 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VHL | - | - | - | - |
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Text-mined citations for rs5030804 ...
HelpRecord last updated Apr 20, 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.