chr3-10142088-C-T

Position:

• chr3-10142088-C-T

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
• Clinical Significance: Benign reviewed by expert panel P:2 U:14 B:11
• Conservation: PhyloP100: 1.47

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.241C>T	p.Pro81Ser	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.241C>T	p.Pro81Ser	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.241C>T	p.Pro81Ser	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.311C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.241C>T	p.Pro81Ser	missense_variant	1/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152206 Hom.: 0 Cov.: 33

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: 46 AN: 230188 Hom.: 0 AF XY: 0.000196 AC XY: 25 AN XY: 127600

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.: 1 Cov.: 32 AF XY: 0.000337 AC XY: 244 AN XY: 723100

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: 53 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.000350 AC XY: 26 AN XY: 74356

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.: 0

Bravo AF: 0.000348

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000590 AC: 5

ExAC AF: 0.000175 AC: 21

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2 Uncertain:14 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1 Uncertain:5 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 11, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2002	- -
Benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jan 02, 2025	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Labs, University Health Network	Sep 08, 2020	- -
Likely benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Oct 01, 2016	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Benign, reviewed by expert panel	curation	ClinGen VHL Variant Curation Expert Panel, ClinGen	Jun 25, 2024	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 29, 2022	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). -

not provided Uncertain:3 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 26, 2024	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 02, 2017	- -
Likely benign, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2021	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 06, 2023	BS1, BP5 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	VHL: PM1, PP3, BP2, BS4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 19, 2020	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:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 22, 2021	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 25, 2022	- -

Enchondromatosis Pathogenic:1

Likely pathogenic, flagged submission

research

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

-

- -

Chuvash polycythemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jul 06, 2022

ACMG classification criteria: PS3 supporting -

Hepatoblastoma Uncertain:1

Uncertain significance, no assertion criteria provided

research

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

-

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	1.7	L;L
PrimateAI	Pathogenic	0.88	D
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	T
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

Other links and lift over

dbSNP: rs104893829; hg19: chr3-10183772; COSMIC: COSV56546019; COSMIC: COSV56546019;