rs5030808

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000551.4(VHL):c.277G>A(p.Gly93Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G93C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.04

Publications

25 publications found

Variant links:

COSMIC-nc: COSV56545729

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

VHL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 33 uncertain in NM_000551.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-10142124-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 223175.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 3-10142124-G-A is Pathogenic according to our data. Variant chr3-10142124-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
VHL	NM_000551.4 link	c.277G>A	p.Gly93Ser	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2 link	c.277G>A	p.Gly93Ser	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3 link	c.277G>A	p.Gly93Ser	missense_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1 link	n.347G>A		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.277G>A	p.Gly93Ser	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448564

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721096

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:

33460

American (AMR)

AF:

0.00

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.0000244

AC:

AN:

40900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111618

Other (OTH)

AF:

0.00

AC:

AN:

60174

⚠️ 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000695

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:2

Dec 15, 2021

Clinical Genomics Labs, University Health Network

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 26, 2016

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Chuvash polycythemia

Pathogenic:1

Nov 30, 2021

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pheochromocytoma

Pathogenic:1

May 09, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Pathogenic:1

Sep 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 93 of the VHL protein (p.Gly93Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with von Hippel-Lindau (VHL) syndrome (PMID: 8707293, 9329368, 12000816, 17661816, 17922902). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.490G>A. ClinVar contains an entry for this variant (Variation ID: 2237). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Aug 05, 2024

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with VHLS and/or pheochromocytoma and has been reported to occur de novo in multiple individuals. This variant is also referred to as c.490G>A in published literature. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Mar 05, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G93S pathogenic mutation (also known as c.277G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 277. The glycine at codon 93 is replaced by serine, an amino acid with similar properties. This alteration has been reported in families with Von Hippel-Lindau (VHL) with pheochromocytomas as well as in individuals with isolated pheochromocytomas (Zbar B et al. Hum Mutat. 1996;8(4):348-57; Neumann HP et al. N Engl J Med. 2002 May 9;346(19):1459-66). Of note, this alteration is also known as c.490G>A in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.2

M;M

PhyloP100

6.0

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;D

Vest4

0.77

MutPred

0.96

Loss of glycosylation at P97 (P = 0.0728);Loss of glycosylation at P97 (P = 0.0728);

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

4.2

PromoterAI

0.057

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.98

Mutation Taster

=1/99

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over