3-10142055-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2_SupportingPS4_Moderate

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.3(VHL):c.208G>T (p.Glu70Ter) variant in VHL is a truncating variant. This variant causes a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The variant has been reported in 6 unrelated probands and/or families meeting either VHL Type 1 or affected with VHL-related cancers. CIViC Evidence IDs (https://civicdb.org): 9266,5361,5445,5035,6059,8209 and PMIDs: 18446368, 8707293, 20660572, 9829911, 7728151, 11148816. (PS4_Moderate)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 (due to a single variant present) (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/CA16602179/MONDO:0008667/078

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VHL
NM_000551.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 2.17

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 Pathogenic. Variant got 11 ACMG points.

PVS1

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

PS4

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

PM2

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.208G>T	p.Glu70*	stop_gained	Exon 1 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 link	c.208G>T	p.Glu70*	stop_gained	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3 link	c.208G>T	p.Glu70*	stop_gained	Exon 1 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 link	n.278G>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.208G>T	p.Glu70*	stop_gained	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453984

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:2

Aug 01, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2024

ClinGen VHL Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The variant NM_000551.3(VHL):c.208G>T (p.Glu70Ter) variant in VHL is a truncating variant. This variant causes a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The variant has been reported in 6 unrelated probands and/or families meeting either VHL Type 1 or affected with VHL-related cancers. CIViC Evidence IDs (https://civicdb.org): 9266,5361,5445,5035,6059,8209 and PMIDs: 18446368, 8707293, 20660572, 9829911, 7728151, 11148816. (PS4_Moderate) 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 (due to a single variant present) (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). -

not provided

Pathogenic:1

Oct 03, 2017

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Oct 03, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E70* pathogenic mutation (also known as c.208G>T) is located in coding exon 1 of the VHL gene, and results from a G to T substitution at nucleotide position 208. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This alteration was first identified in an individual with von Hippel-Lindau disease Type 1 (Chen F, Hum. Mutat. 1995 ; 5(1):66-75), and is also known as 421G>T and Glu70stop in the literature. In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.93

Vest4

0.86

GERP RS

4.6

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

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