The variant NM_000551.4(VHL):c.241C>T (p.Pro81Ser) is a missense variant in the first exon of the VHL gene. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0004281 (543/1179690 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). Therefore this variant meets the criterion for (BA1) and is classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024).
ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.241C>T (p.Pro81Ser)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Benign
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000551.4(VHL):c.241C>T (p.Pro81Ser)
Variation ID: 2233 Accession: VCV000002233.71
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p25.3 3: 10142088 (GRCh38) [ NCBI UCSC ] 3: 10183772 (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 Apr 4, 2013 Oct 20, 2024 Jun 25, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000551.4:c.241C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Pro81Ser missense NM_001354723.2:c.241C>T NP_001341652.1:p.Pro81Ser missense NM_198156.3:c.241C>T NP_937799.1:p.Pro81Ser missense NC_000003.12:g.10142088C>T NC_000003.11:g.10183772C>T NG_008212.3:g.5454C>T LRG_322:g.5454C>T LRG_322t1:c.241C>T LRG_322p1:p.Pro81Ser P40337:p.Pro81Ser - Protein change
- P81S
- Other names
-
p.P81S:CCG>TCG
NM_000551.4(VHL):c.241C>T
- Canonical SPDI
- NC_000003.12:10142087:C:T
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00020
Exome Aggregation Consortium (ExAC) 0.00021
Trans-Omics for Precision Medicine (TOPMed) 0.00035
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00039
The Genome Aggregation Database (gnomAD) 0.00039
- Links
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 |
832 | 2004 | |
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. |
|---|---|---|---|---|
| Benign (11) |
reviewed by expert panel
|
Jun 25, 2024 | RCV000002321.36 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jan 25, 2022 | RCV000115744.21 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 31, 2024 | RCV000213077.24 | |
| Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Feb 6, 2023 | RCV000656990.43 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000418681.9 | |
| Benign (1) |
criteria provided, single submitter
|
Feb 1, 2024 | RCV001080004.14 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001843451.9 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Oct 12, 2023 | RCV002467489.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jul 6, 2022 | RCV003225718.8 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(Jun 25, 2024)
|
reviewed by expert panel
Method: curation
|
Von Hippel-Lindau syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen VHL Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV005187310.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
Comment:
The variant NM_000551.4(VHL):c.241C>T (p.Pro81Ser) is a missense variant in the first exon of the VHL gene. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD … (more)
The variant NM_000551.4(VHL):c.241C>T (p.Pro81Ser) is a missense variant in the first exon of the VHL gene. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0004281 (543/1179690 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). Therefore this variant meets the criterion for (BA1) and is classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). (less)
|
|
|
Uncertain significance
(Mar 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000540657.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Several reports describe as LB/non-pathogenic; ExAC: 0.04% (19/53684) European chromosomes (less)
Method: Genome/Exome Filtration
|
|
|
Likely benign
(Oct 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000805331.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
|
|
|
Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001136311.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001311112.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Sep 08, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
|
Clinical Genomics Labs, University Health Network
Accession: SCV001950150.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Uncertain significance
(Mar 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002071720.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the VHL gene demonstrated a sequence change, c.241C>T, in exon 1 that results in an amino acid change, p.Pro81Ser. This sequence … (more)
DNA sequence analysis of the VHL gene demonstrated a sequence change, c.241C>T, in exon 1 that results in an amino acid change, p.Pro81Ser. This sequence change has been described in the gnomAD database with a frequency of 0.04% in the European sub-population (dbSNP rs104893829). The p.Pro81Ser change has been reported in individuals with Von-Hippel Lindau-related cancers (PMIDs: 28503092, 19906784, 11106358, 9829911, 12414898, 8634692; Glavac 1996, Glasker 1999, Haitz 2015). This sequence change has been identified in two families that also had a likely pathogenic VHL variant in cis with this sequence change (PMIDs: 19906784, 12414898), and one family with a large deletion of the entire VHL gene in trans with this sequence change, in which the p.Pro81Ser change did not segregate with disease (PMID: 19906784). The p.Pro81Ser change has also been identified in three unrelated individuals with hemangioblastoma or renal cell carcinoma (Haitz 2015; PMID: 28503092, 11106358). Relatives of these individuals who carried the sequence change were not affected. Functional studies have suggested both normal protein activity (PMID: 19228690), and lack of ubiquitination, reduced DNA damage response, and resistance to ionizing radiation-induced apoptosis (Li 2002; PMID: 23990666) in the presence of this sequence change. The p.Pro81Ser change affects a highly conserved amino acid residue located in a domain of the VHL protein that is known to be functional. The p.Pro81Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro81Ser change remains unknown at this time. (less)
|
|
|
Uncertain significance
(Jan 25, 2022)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002534150.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The VHL c.241C>T (p.P81S) variant has been reported in individuals with features of Von Hippel-Lindau syndrome, including renal cell carcinoma, hemangioblastoma, and paraganglioma (PMID: 11106358, … (more)
The VHL c.241C>T (p.P81S) variant has been reported in individuals with features of Von Hippel-Lindau syndrome, including renal cell carcinoma, hemangioblastoma, and paraganglioma (PMID: 11106358, 8634692, 9829911, 19906784, 28503092, 27527340, 30877234, among others). The p.P81S has been reported to segregate with disease in three families with isolated pheochromocytomas, termed VHL type 2C, however these individuals carried another pathogenic VHL variant, p.Leu188Val, in cis (PMID: 7563486, 8772572, 12414898). This variant has been reported as hemizygous in an individual with hemangioblastomas, who carried a full VHL gene deletion in trans (PMID: 19906784). Also described as 454C>T in the literature, this variant has been found in unaffected family members and in healthy individuals (PMID: 11106358, 28503092, 25637381). Based on this, it has been proposed that this variant may be a low-penetrance pathogenic variant (PMID: 11106358, 28503092, 19228690) or that it may modify the phenotype when found with other high penetrance VHL pathogenic variants (PMID: 12414898), while others describe it as a non-disease causing variant (PMID:19906784). It was observed in 53/119480 chromosomes of the Non-Finnish European subpopulation, with no homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org). This frequency is higher than expected for a disease-causing VHL variant. The variant has been reported in ClinVar (Variation ID 2233). In silico tools suggest the impact of the variant on protein function is inconclusive. Functional studies have shown activity close to wildtype (PMID: 19228690), or a slight reduction to target protein binding with minimal impact to the protein complex functionality (PMID: 22234250). Another study suggested this variant may alter DNA damage response and suppress ionizing radiation-induced apoptosis (PMID: 23990666). The current evidence is conflicting and insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
|
Likely benign
(Dec 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149653.15
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
See Variant Classification Assertion Criteria.
|
|
|
Uncertain significance
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011313.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Uncertain significance
(Aug 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175351.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The VHL c.241C>T variant is a single nucleotide change in exon 1/3 of the VHL gene, which is predicted to change the amino acid proline … (more)
The VHL c.241C>T variant is a single nucleotide change in exon 1/3 of the VHL gene, which is predicted to change the amino acid proline at position 81 in the protein to serine. This variant is situated at the alpha-beta domain interface (PM1). The population frequency is higher than expected for a disease-causing VHL variant (gnomAD 0.035%, 53/152206) (PM2 Not Met). This variant has been reported in several families and individuals with VHL-related syndromes, including RCC, hemangioblastoma, and paraganglioma (PMID: 28503092, 8707293, 9829911, 10567493, 11106358) (PS4). Erlic et al. (PMID: 19906784) reported an affected individual who had inherited this variant from his unaffected father, but who also had an in trans, de novo deletion of the entire VHL gene (BP2). Alosi et al. (PMID: 28503092) reported a kindred with 5 carriers of the variant and only one family member was affected with early onset renal clear cell cancer, suggesting that suggesting that the variant does not segregate with disease (BS4) or it may be a variant of variable penetrance. In silico tools suggest the impact of the variant on protein function is inconclusive. Functional studies have shown activity close to wildtype (PMID: 19228690), or a slight reduction to target protein binding with minimal impact to the protein complex functionality, except when in conjunction with another VHL variant (PMID: 22234250). The variant has been reported in dbSNP (rs104893829) and HGMD (CM951274). The variant has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID:2233). (less)
|
|
|
Uncertain significance
(Feb 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226048.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
BS1, BP5
Number of individuals with the variant: 17
|
|
|
Benign
(Feb 01, 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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254650.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
|
|
|
Uncertain significance
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002552399.4
First in ClinVar: Jul 27, 2022 Last updated: Aug 04, 2024 |
|
|
|
Likely benign
(Nov 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001153778.25
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Comment:
VHL: PM1, PP3, BP2, BS4
Number of individuals with the variant: 1
|
|
|
Likely benign
(Oct 01, 2016)
|
criteria provided, single submitter
Method: research
|
von Hippel-Lindau syndrome
Affected status: no
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: CSER - NEXT Medicine variant annotation
Accession: SCV000190677.2 First in ClinVar: Dec 06, 2014 Last updated: Mar 23, 2018 |
Comment:
Found in patient having exome sequencing for an unrelated indication. No known history of von Hippel-Lindau syndrome. This interpretation considers GERP score and allele frequency … (more)
Found in patient having exome sequencing for an unrelated indication. No known history of von Hippel-Lindau syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. (less)
|
|
|
Likely benign
(Sep 16, 2018)
|
criteria provided, single submitter
Method: research
|
not provided
Affected status: no
Allele origin:
germline
|
Gharavi Laboratory, Columbia University
Accession: SCV000920742.1
First in ClinVar: Jun 09, 2019 Last updated: Jun 09, 2019 |
|
|
|
Uncertain significance
(Jul 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Chuvash polycythemia
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807914.2
First in ClinVar: Mar 04, 2023 Last updated: May 06, 2023 |
Comment:
ACMG classification criteria: PS3 supporting
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Uncertain significance
(Jul 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV000890934.4
First in ClinVar: Mar 19, 2019 Last updated: Sep 01, 2023 |
Comment:
The VHL c.241C>T (p.Pro81Ser) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The variant is located in a mutational hotspot … (more)
The VHL c.241C>T (p.Pro81Ser) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The variant is located in a mutational hotspot (COSMIC database). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies have shown mixed effects. Some functional studies have concluded that the variant behaves similar to the wild-type (Knauth 2009), whereas others suggest this variant may lead to reduced DNA damage response and resistance to ionizing radiation induced apoptosis (Li 2002, Desimone 2013). The Pro81Ser change has been reported in several individuals and families with Von Hippel Lindau-related cancers (Glavac 1996, Stolle 1998, Glasker 1999, Hes 2000, Weirich 2002, Erlic 2010, Haitz 2015, Alosi 2017). The Pro81Ser variant did not segregate with disease in a family with Von Hippel Lindau (Erlic 2009). In another family with several affected individuals, the variant was found to co-segregate in cis with another missense change in VHL (Weirich 2002). Since supporting evidence is conflicting, the clinical significance of this alteration remains unclear. It has therefore been classified as of uncertain significance. (less)
|
|
|
Likely Benign
(Feb 05, 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: SCV004841639.1
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)
|
Number of individuals with the variant: 106
|
|
|
Likely benign
(Mar 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000212872.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Uncertain significance
(Feb 26, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Von Hippel-Lindau syndrome
Affected status: unknown
Allele origin:
germline
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000264680.1
First in ClinVar: Mar 08, 2016 Last updated: Mar 08, 2016 |
Number of individuals with the variant: 3
|
|
|
Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000505320.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Nov 01, 2002)
|
no assertion criteria provided
Method: literature only
|
VON HIPPEL-LINDAU SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022479.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2020 |
Comment on evidence:
In 6 members of a German family in which the L188V mutation in the VHL gene (608537.0014) had previously been identified in association with von … (more)
In 6 members of a German family in which the L188V mutation in the VHL gene (608537.0014) had previously been identified in association with von Hippel-Lindau syndrome type 2C (VHLS; 193300), Weirich et al. (2002) identified a 454C-T transition in exon 1 of the VHL gene, resulting in a pro81-to-ser (P81S) mutation. The concurrent P81S mutation was identified by novel screening approaches, including denaturing high-performance liquid chromatography (DHPLC) and sequencing. The 2 mutations cosegregated with the syndrome. Weirich et al. (2002) discussed the possible impact of the mutations on protein function and phenotype. (less)
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: research
|
Hepatoblastoma
Affected status: yes
Allele origin:
germline
|
Molecular Oncology - Human Genetics Lab, University of Sao Paulo
Accession: SCV002103110.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
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Likely benign
(Oct 02, 2015)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053257.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
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Likely pathogenic
(-)
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Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Enchondromatosis
Affected status: yes
Allele origin:
paternal
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Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine
Accession: SCV002764243.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Several reports describe as LB/non-pathogenic; ExAC: 0.04% (19/53684) European chromosomes
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
DNA sequence analysis of the VHL gene demonstrated a sequence change, c.241C>T, in exon 1 that results in an amino acid change, p.Pro81Ser. This sequence change has been described in the gnomAD database with a frequency of 0.04% in the European sub-population (dbSNP rs104893829). The p.Pro81Ser change has been reported in individuals with Von-Hippel Lindau-related cancers (PMIDs: 28503092, 19906784, 11106358, 9829911, 12414898, 8634692; Glavac 1996, Glasker 1999, Haitz 2015). This sequence change has been identified in two families that also had a likely pathogenic VHL variant in cis with this sequence change (PMIDs: 19906784, 12414898), and one family with a large deletion of the entire VHL gene in trans with this sequence change, in which the p.Pro81Ser change did not segregate with disease (PMID: 19906784). The p.Pro81Ser change has also been identified in three unrelated individuals with hemangioblastoma or renal cell carcinoma (Haitz 2015; PMID: 28503092, 11106358). Relatives of these individuals who carried the sequence change were not affected. Functional studies have suggested both normal protein activity (PMID: 19228690), and lack of ubiquitination, reduced DNA damage response, and resistance to ionizing radiation-induced apoptosis (Li 2002; PMID: 23990666) in the presence of this sequence change. The p.Pro81Ser change affects a highly conserved amino acid residue located in a domain of the VHL protein that is known to be functional. The p.Pro81Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro81Ser change remains unknown at this time.
Comment:
See Variant Classification Assertion Criteria.
Comment:
The VHL c.241C>T variant is a single nucleotide change in exon 1/3 of the VHL gene, which is predicted to change the amino acid proline at position 81 in the protein to serine. This variant is situated at the alpha-beta domain interface (PM1). The population frequency is higher than expected for a disease-causing VHL variant (gnomAD 0.035%, 53/152206) (PM2 Not Met). This variant has been reported in several families and individuals with VHL-related syndromes, including RCC, hemangioblastoma, and paraganglioma (PMID: 28503092, 8707293, 9829911, 10567493, 11106358) (PS4). Erlic et al. (PMID: 19906784) reported an affected individual who had inherited this variant from his unaffected father, but who also had an in trans, de novo deletion of the entire VHL gene (BP2). Alosi et al. (PMID: 28503092) reported a kindred with 5 carriers of the variant and only one family member was affected with early onset renal clear cell cancer, suggesting that suggesting that the variant does not segregate with disease (BS4) or it may be a variant of variable penetrance. In silico tools suggest the impact of the variant on protein function is inconclusive. Functional studies have shown activity close to wildtype (PMID: 19228690), or a slight reduction to target protein binding with minimal impact to the protein complex functionality, except when in conjunction with another VHL variant (PMID: 22234250). The variant has been reported in dbSNP (rs104893829) and HGMD (CM951274). The variant has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID:2233).
Comment:
BS1, BP5
Comment:
VHL: PM1, PP3, BP2, BS4
Comment:
Found in patient having exome sequencing for an unrelated indication. No known history of von Hippel-Lindau syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Comment:
ACMG classification criteria: PS3 supporting
Comment:
The VHL c.241C>T (p.Pro81Ser) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The variant is located in a mutational hotspot (COSMIC database). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies have shown mixed effects. Some functional studies have concluded that the variant behaves similar to the wild-type (Knauth 2009), whereas others suggest this variant may lead to reduced DNA damage response and resistance to ionizing radiation induced apoptosis (Li 2002, Desimone 2013). The Pro81Ser change has been reported in several individuals and families with Von Hippel Lindau-related cancers (Glavac 1996, Stolle 1998, Glasker 1999, Hes 2000, Weirich 2002, Erlic 2010, Haitz 2015, Alosi 2017). The Pro81Ser variant did not segregate with disease in a family with Von Hippel Lindau (Erlic 2009). In another family with several affected individuals, the variant was found to co-segregate in cis with another missense change in VHL (Weirich 2002). Since supporting evidence is conflicting, the clinical significance of this alteration remains unclear. It has therefore been classified as of uncertain significance.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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. |
Comment:
The variant NM_000551.4(VHL):c.241C>T (p.Pro81Ser) is a missense variant in the first exon of the VHL gene. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0004281 (543/1179690 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). Therefore this variant meets the criterion for (BA1) and is classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024).
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Several reports describe as LB/non-pathogenic; ExAC: 0.04% (19/53684) European chromosomes
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
DNA sequence analysis of the VHL gene demonstrated a sequence change, c.241C>T, in exon 1 that results in an amino acid change, p.Pro81Ser. This sequence change has been described in the gnomAD database with a frequency of 0.04% in the European sub-population (dbSNP rs104893829). The p.Pro81Ser change has been reported in individuals with Von-Hippel Lindau-related cancers (PMIDs: 28503092, 19906784, 11106358, 9829911, 12414898, 8634692; Glavac 1996, Glasker 1999, Haitz 2015). This sequence change has been identified in two families that also had a likely pathogenic VHL variant in cis with this sequence change (PMIDs: 19906784, 12414898), and one family with a large deletion of the entire VHL gene in trans with this sequence change, in which the p.Pro81Ser change did not segregate with disease (PMID: 19906784). The p.Pro81Ser change has also been identified in three unrelated individuals with hemangioblastoma or renal cell carcinoma (Haitz 2015; PMID: 28503092, 11106358). Relatives of these individuals who carried the sequence change were not affected. Functional studies have suggested both normal protein activity (PMID: 19228690), and lack of ubiquitination, reduced DNA damage response, and resistance to ionizing radiation-induced apoptosis (Li 2002; PMID: 23990666) in the presence of this sequence change. The p.Pro81Ser change affects a highly conserved amino acid residue located in a domain of the VHL protein that is known to be functional. The p.Pro81Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro81Ser change remains unknown at this time.
Comment:
See Variant Classification Assertion Criteria.
Comment:
The VHL c.241C>T variant is a single nucleotide change in exon 1/3 of the VHL gene, which is predicted to change the amino acid proline at position 81 in the protein to serine. This variant is situated at the alpha-beta domain interface (PM1). The population frequency is higher than expected for a disease-causing VHL variant (gnomAD 0.035%, 53/152206) (PM2 Not Met). This variant has been reported in several families and individuals with VHL-related syndromes, including RCC, hemangioblastoma, and paraganglioma (PMID: 28503092, 8707293, 9829911, 10567493, 11106358) (PS4). Erlic et al. (PMID: 19906784) reported an affected individual who had inherited this variant from his unaffected father, but who also had an in trans, de novo deletion of the entire VHL gene (BP2). Alosi et al. (PMID: 28503092) reported a kindred with 5 carriers of the variant and only one family member was affected with early onset renal clear cell cancer, suggesting that suggesting that the variant does not segregate with disease (BS4) or it may be a variant of variable penetrance. In silico tools suggest the impact of the variant on protein function is inconclusive. Functional studies have shown activity close to wildtype (PMID: 19228690), or a slight reduction to target protein binding with minimal impact to the protein complex functionality, except when in conjunction with another VHL variant (PMID: 22234250). The variant has been reported in dbSNP (rs104893829) and HGMD (CM951274). The variant has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID:2233).
Comment:
BS1, BP5
Comment:
VHL: PM1, PP3, BP2, BS4
Comment:
Found in patient having exome sequencing for an unrelated indication. No known history of von Hippel-Lindau syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Comment:
ACMG classification criteria: PS3 supporting
Comment:
The VHL c.241C>T (p.Pro81Ser) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The variant is located in a mutational hotspot (COSMIC database). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies have shown mixed effects. Some functional studies have concluded that the variant behaves similar to the wild-type (Knauth 2009), whereas others suggest this variant may lead to reduced DNA damage response and resistance to ionizing radiation induced apoptosis (Li 2002, Desimone 2013). The Pro81Ser change has been reported in several individuals and families with Von Hippel Lindau-related cancers (Glavac 1996, Stolle 1998, Glasker 1999, Hes 2000, Weirich 2002, Erlic 2010, Haitz 2015, Alosi 2017). The Pro81Ser variant did not segregate with disease in a family with Von Hippel Lindau (Erlic 2009). In another family with several affected individuals, the variant was found to co-segregate in cis with another missense change in VHL (Weirich 2002). Since supporting evidence is conflicting, the clinical significance of this alteration remains unclear. It has therefore been classified as of uncertain significance.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. | Ben Aim L | Journal of medical genetics | 2019 | PMID: 30877234 |
| Genotype-Phenotype Correlation of Hereditary Erythrocytosis Mutations, a single center experience. | Oliveira JL | American journal of hematology | 2018 | PMID: 29790589 |
| Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of the VHL Mutation p.P81S (c.241C>T). | Alosi D | Current genomics | 2017 | PMID: 28503092 |
| Clinical and molecular characteristics of East Asian patients with von Hippel-Lindau syndrome. | Wong M | Chinese journal of cancer | 2016 | PMID: 27527340 |
| Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Pleiotropic effects of the trichloroethylene-associated P81S VHL mutation on metabolism, apoptosis, and ATM-mediated DNA damage response. | Desimone MC | Journal of the National Cancer Institute | 2013 | PMID: 23990666 |
| New insights into von Hippel-Lindau function highlighted by investigation of the trichloroethylene-induced p.P81S hotspot mutation. | Neckers L | Journal of the National Cancer Institute | 2013 | PMID: 23990664 |
| The interaction of the von Hippel-Lindau tumor suppressor and heterochromatin protein 1. | Lai Y | Archives of biochemistry and biophysics | 2012 | PMID: 22234250 |
| Clinical and molecular features of familial and sporadic cases of von Hippel-Lindau disease from Mexico. | Chacon-Camacho OF | Clinical & experimental ophthalmology | 2010 | PMID: 20447124 |
| 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 |
| 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 |
| 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 |
| 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 |
| Cryptic von Hippel-Lindau disease: germline mutations in patients with haemangioblastoma only. | Hes FJ | Journal of medical genetics | 2000 | PMID: 11106358 |
| 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 |
| The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system. | Gläsker S | Journal of neurology, neurosurgery, and psychiatry | 1999 | PMID: 10567493 |
| 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 |
| Germline mutations in the von Hippel-Lindau disease (VHL) gene in Japanese VHL. Clinical Research Group for VHL in Japan. | - | Human molecular genetics | 1995 | PMID: 8634692 |
| 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 |
| http://docm.genome.wustl.edu/variants/ENST00000256474:c.241C>T | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/416afbe6-3dd6-40d9-9e61-d3c54b017b5e | - | - | - | - |
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Text-mined citations for rs104893829 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.