chr3-10142055-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 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

Publications

29 publications found

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 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, G2P
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

VHL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VHL	NM_000551.4	MANE Select	c.208G>T	p.Glu70*	stop_gained	Exon 1 of 3	NP_000542.1	A0A024R2F2
VHL	NM_001354723.2		c.208G>T	p.Glu70*	stop_gained	Exon 1 of 3	NP_001341652.1	A0A8Q3WL21
VHL	NM_198156.3		c.208G>T	p.Glu70*	stop_gained	Exon 1 of 2	NP_937799.1	A0A0S2Z4K1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VHL	ENST00000256474.3	TSL:1 MANE Select	c.208G>T	p.Glu70*	stop_gained	Exon 1 of 3	ENSP00000256474.3	P40337-1
VHL	ENST00000345392.3	TSL:1	c.208G>T	p.Glu70*	stop_gained	Exon 1 of 2	ENSP00000344757.2	P40337-2
VHL	ENST00000477538.2	TSL:1	n.254G>T		non_coding_transcript_exon	Exon 1 of 3

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

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

African (AFR)

AF:

0.00

AC:

AN:

33402

American (AMR)

AF:

0.00

AC:

AN:

44232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.00

AC:

AN:

85652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110472

Other (OTH)

AF:

0.0000166

AC:

AN:

60162

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Von Hippel-Lindau syndrome (2)

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.93

PhyloP100

2.2

Vest4

0.86

GERP RS

4.6

PromoterAI

-0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over