rs119103277

Positions:

• chr3-10142110-G-A
• chr3-10142110-G-C
• chr3-10142110-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2_Supporting PS4 PVS1

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.4(VHL):c.263G>A (p.Trp88Ter) in VHL is a truncating variant. This variant causes a premature stop codon in a biologically-relevant-exon predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been identified in at least 9 unrelated probands (and other related family members not counted within each) all meeting Danish VHL criteria, from literature evaluated in both CIViC and Hypothes.is VHL datasets. CIViC EIDs (https://civicdb.org): 8292;7606;5776;9374;6806;6538. This corresponds to Strong evidence (5-15 probands) (PS4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as 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/CA020197/MONDO:0008667/078

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 6.04

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.263G>A	p.Trp88Ter	stop_gained	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.263G>A	p.Trp88Ter	stop_gained	1/3
VHL	NM_198156.3	c.263G>A	p.Trp88Ter	stop_gained	1/2
VHL	NR_176335.1	n.333G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.263G>A	p.Trp88Ter	stop_gained	1/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Labs, University Health Network	Apr 30, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen VHL Variant Curation Expert Panel, ClinGen	Jun 25, 2024	The variant NM_000551.4(VHL):c.263G>A (p.Trp88Ter) in VHL is a truncating variant. This variant causes a premature stop codon in a biologically-relevant-exon predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been identified in at least 9 unrelated probands (and other related family members not counted within each) all meeting Danish VHL criteria, from literature evaluated in both CIViC and Hypothes.is VHL datasets. CIViC EIDs (https://civicdb.org): 8292;7606;5776;9374;6806;6538. This corresponds to Strong evidence (5-15 probands) (PS4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as 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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 18, 2022

This sequence change creates a premature translational stop signal (p.Trp88*) in the VHL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VHL are known to be pathogenic (PMID: 8956040, 12202531, 29891534, 31350093). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 182978). This premature translational stop signal has been observed in individual(s) with clinical features of von Hippel–Lindau syndrome (PMID: 10408776, 27527340). This variant is not present in population databases (gnomAD no frequency). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2023

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.476G>A; p.(W159*) and p.(W129*); This variant is associated with the following publications: (PMID: 27527340, 22357542, 28650583, 11058902, 10408776, 24446253, 25027579, 25069792, 20233476, 27617348, 28849724, 32117777, 34847388, 35055428) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2023

The p.W88* pathogenic mutation (also known as c.263G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 263. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. This mutation has been identified in multiple individuals meeting clinical diagnostic criteria for von Hippel-Lindau disease (Wu P et al. J. Hum. Genet. 2012 Apr; 57(4):238-43). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with VHL-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A
Vest4		0.91
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs119103277; hg19: chr3-10183794; COSMIC: COSV56545932; COSMIC: COSV56545932;