3-10142088-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA020148/MONDO:0008667/078

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 1 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:2U:13B:12

Conservation

PhyloP100: 1.47

Variant links:

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

VHL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.241C>T	p.Pro81Ser	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 link	c.241C>T	p.Pro81Ser	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3 link	c.241C>T	p.Pro81Ser	missense_variant	Exon 1 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 link	n.311C>T		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 link	c.241C>T	p.Pro81Ser	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000200

AC:

AN:

230188

Hom.:

AF XY:

0.000196

AC XY:

AN XY:

127600

show subpopulations

Gnomad AFR exome

AF:

0.0000715

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000413

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.000353

AC:

513

AN:

1453020

Hom.:

Cov.:

AF XY:

0.000337

AC XY:

244

AN XY:

723100

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000442

Gnomad4 NFE exome

AF:

0.000446

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000348

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000567

Hom.:

Bravo

AF:

0.000348

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000590

AC:

ExAC

AF:

0.000175

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2Uncertain:13Benign:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:1Uncertain:5Benign:5

Feb 26, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2016

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

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. -

Jan 02, 2025

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VHL c.241C>T (p.Pro81Ser) missense change has a maximum subpopulation frequency of 0.046% in gnomAD v4.1.0 including one homozygote (https://gnomad.broadinstitute.org/). The GroupMax filtering allele frequency in gnomAD V4.1.0 is higher than the frequency threshold for a variant causing Von Hippel Lindau disease as defined by the ClinGen VHL Variant Curation Expert Panel (https://cspec.genome.network/cspec/ui/svi/doc/GN078). Therefore, reports of this variant in individuals with Von Hippel Lindau-related cancers are not expected to be causal. In summary, this variant meets criteria to be classified as benign. -

Sep 08, 2020

Clinical Genomics Labs, University Health Network

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Nov 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 25, 2024

ClinGen VHL Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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). -

not provided

Uncertain:3Benign:4

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 06, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP5 -

Dec 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Oct 02, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VHL c.241C>T (p.Pro81Ser) variant has been reported in the published literature in individuals with the features of von Hippel Lindau syndrome (PMIDs: 37937776 (2023), 36175619 (2022), 35495172 (2022), 34628056 (2021), 28503092 (2017), 19906784 (2010), 12414898 (2002), 11106358 (2000), 10567493 (1999), 9829911 (1998), 8707293 (1996), 8956040 (1996), and 8634692 (1995)). In some cases, these individuals were also positive for a pathogenic VHL variant that may have been primarily or wholly responsible for the disease phenotype (PMIDs: 19906784 (2010), 12414898 (2002), and 9829911 (1998)). Family studies examining the segregation of this variant with disease are inconclusive and this variant has been identified in unaffected elderly relatives of affected individuals (PMIDs: 28503092 (2017), 19906784 (2010), and 11106358 (2000)). However, these studies are not inconsistent with reduced penetrance or a modifier role for this variant (PMID: 28503092 (2017)). Functional studies suggest that this variant may have a slightly destabilizing effect (PMID: 19228690 (2009)), evade degradation (PMID: 36813923 (2023)), and prevents the degradation of other proteins (PMID: 11739384 (2002)). Consequently, this variant may contribute to tumorigenesis by promoting cellular proliferation, interfering with the expression of DNA damage response genes, and suppressing apoptosis (PMIDs: 23990666 (2013) and 36175619 (2022)). The frequency of this variant in the general population, 0.00065 (30/46190 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VHL: PM1, PP3, BP2, BS4 -

not specified

Uncertain:2Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 19, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Mar 22, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 25, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Enchondromatosis

Pathogenic:1

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

Chuvash polycythemia

Uncertain:1

Jul 06, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting -

Hepatoblastoma

Uncertain:1

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.99

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Benign

1.7

L;L

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.2

D;D

REVEL

Pathogenic

0.68

Sift

Benign

0.038

.;D

Sift4G

Benign

0.39

T;T

Polyphen

0.94

P;D

Vest4

0.35

MVP

1.0

MPC

0.82

ClinPred

0.33

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over