3-10142111-G-T

Variant names:

• chr3-10142111-G-T
• rs869025622
• NM_000551.4:c.264G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3_Supporting PM1 PP3 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.4(VHL):c.264G>T (p.Trp88Cys) is a missense variant predicted to cause substitution of Cysteine for Tryptophan at position 88. There is one variant present in gnomAD v4.1.0. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is not calculated. PM2_Supporting can be applied for variants with <= 0.0000015 (0.00015%) frequency in gnomAD, or if no GroupMax Filtering Allele Frequency is calculated (PM2_Supporting). Three commercial laboratories report at total of 6 cases harboring this variant, and sum to a total of 4 points (Moderate). Ambry: Case1 (0.5 points): 15-20yo with retinal hemangioblastomas; Case 2(0.5 points) 15-20yo with bilateral retinal hemangioblastomas; Gene DX: Case1(1 point) bilateral clear cell renal cell carcinoma and hemangioblastoma as a minor. Invitae: Case 1(0.5 points) Hemangioblastoma of thoracic spine and retinal angioma in 20s. Case 2 (1 point) Hemangioblastoma in CNS x2, pancreatic cysts, venal cyst in 30s. Case 3 (0.5 points) multiple bilateral enhancing cystic and solid renal masses and multiple pancreatic cystic lesions, highly suspicious for VHL in 30s. (PS4_Moderate). HIF degradation assays in mouse embryonic fibroblasts showed W88C was unable to degrade HIF1a or HIF2a compared to wild type VHL, indicting that this variant impacts protein functions (PMID:21715564)(PS3_Supporting). This variant is located in a mutational hotspot (PMID:35475554). There are multiple other nucleotide and amino acid substitutions at this position in ClinVar, including: NM_000551.4(VHL):c.264G>C (p.Trp88Cys), NM_000551.4(VHL):c.263G>C (p.Trp88Ser), NM_000551.4(VHL):c.262T>A (p.Trp88Arg), NM_000551.4(VHL):c.262T>C (p.Trp88Arg). (PM1). The computational predictor REVEL gives a score of 0.945, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) 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/CA357078/MONDO:0008667/078

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 6.04
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.264G>T	p.Trp88Cys	missense	Exon 1 of 3	NP_000542.1
	VHL	NM_001354723.2		c.264G>T	p.Trp88Cys	missense	Exon 1 of 3	NP_001341652.1
	VHL	NM_198156.3		c.264G>T	p.Trp88Cys	missense	Exon 1 of 2	NP_937799.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.264G>T	p.Trp88Cys	missense	Exon 1 of 3	ENSP00000256474.3
	VHL	ENST00000345392.3	TSL:1	c.264G>T	p.Trp88Cys	missense	Exon 1 of 2	ENSP00000344757.2
	VHL	ENST00000477538.2	TSL:1	n.310G>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721836

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.0000236 AC: 1 AN: 42386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111676

Other (OTH) AF: 0.00 AC: 0 AN: 60258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3

Mar 27, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Trp88Cys variant in VHL has been reported in at least 5 individuals with v on Hippel-Landau syndrome (VHL; Glasker 1999, Clinvar Variation ID: 223171), and was absent from large population studies. In vitro functional studies provide s ome evidence that the p.Trp88Cys variant may impact protein function (Reschestei ner 2011). Computational prediction tools and conservation analysis suggest that the p.Trp88Cys variant may impact the protein. Additionally, other missense va riants at this position (p.Trp88Arg and p.Trp88Ser) have been reported in indivi duals with VHL (Glasker 2001, Rocha 2003, Chen 1995, Ong 2007, Jilg 2012, Stanoj evic 2007, Wong 2016), suggesting that a change at this amino acid position is n ot tolerated. In summary, although additional studies are required to fully esta blish its clinical significance, the p.Trp88Cys variant is likely pathogenic. AC MG/AMP criteria applied (Richards 2015): PM2; PM5; PP3; PS3_supporting; PS4_supp orting.

Feb 26, 2016

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 25, 2024

ClinGen VHL Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The variant NM_000551.4(VHL):c.264G>T (p.Trp88Cys) is a missense variant predicted to cause substitution of Cysteine for Tryptophan at position 88. There is one variant present in gnomAD v4.1.0. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is not calculated. PM2_Supporting can be applied for variants with <= 0.0000015 (0.00015%) frequency in gnomAD, or if no GroupMax Filtering Allele Frequency is calculated (PM2_Supporting). Three commercial laboratories report at total of 6 cases harboring this variant, and sum to a total of 4 points (Moderate). Ambry: Case1 (0.5 points): 15-20yo with retinal hemangioblastomas; Case 2(0.5 points) 15-20yo with bilateral retinal hemangioblastomas; Gene DX: Case1(1 point) bilateral clear cell renal cell carcinoma and hemangioblastoma as a minor. Invitae: Case 1(0.5 points) Hemangioblastoma of thoracic spine and retinal angioma in 20s. Case 2 (1 point) Hemangioblastoma in CNS x2, pancreatic cysts, venal cyst in 30s. Case 3 (0.5 points) multiple bilateral enhancing cystic and solid renal masses and multiple pancreatic cystic lesions, highly suspicious for VHL in 30s. (PS4_Moderate). HIF degradation assays in mouse embryonic fibroblasts showed W88C was unable to degrade HIF1a or HIF2a compared to wild type VHL, indicting that this variant impacts protein functions (PMID:21715564)(PS3_Supporting). This variant is located in a mutational hotspot (PMID:35475554). There are multiple other nucleotide and amino acid substitutions at this position in ClinVar, including: NM_000551.4(VHL):c.264G>C (p.Trp88Cys), NM_000551.4(VHL):c.263G>C (p.Trp88Ser), NM_000551.4(VHL):c.262T>A (p.Trp88Arg), NM_000551.4(VHL):c.262T>C (p.Trp88Arg). (PM1). The computational predictor REVEL gives a score of 0.945, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) 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).

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

Mar 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Trp88 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 8956040, 10567493, 17024664). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 21715564). 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. ClinVar contains an entry for this variant (Variation ID: 223171). This missense change has been observed in individuals with clinical features of von Hippel-Lindau (VHL) syndrome (PMID: 10567493; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 88 of the VHL protein (p.Trp88Cys).

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 03, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W88C variant (also known as c.264G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 264. The tryptophan at codon 88 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in a cohort of over 25,000 individuals who underwent multigene panel testing (eMERGE Consortium. Am J Hum Genet, 2019 09;105:588-605). A similar alteration resulting in the same amino acid change (W88C) but with a different nucleotide change (referred to as 477G/C) has been reported in one individual diagnosed with CNS hemangioblastomas (Gl&auml;sker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67(6):758-62). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.92		Gain of disorder (P = 0.0101)
MVP		0.99
MPC		0.87
ClinPred		1.0	D
GERP RS		5.1
PromoterAI		0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		1.0
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs869025622; hg19: chr3-10183795; COSMIC: COSV56554033; COSMIC: COSV56554033;