chr3-10142179-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_000551.4(VHL):c.332G>A(p.Ser111Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S111I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.02

Publications

33 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: 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 15 ACMG points.

PM1

In a hotspot region, there are 28 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 20 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 chr3-10142178-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 633016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

PP5

Variant 3-10142179-G-A is Pathogenic according to our data. Variant chr3-10142179-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 223186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.332G>A	p.Ser111Asn	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 link	c.332G>A	p.Ser111Asn	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3 link	c.332G>A	p.Ser111Asn	missense_variant	Exon 1 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 link	n.402G>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.332G>A	p.Ser111Asn	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1446050

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719814

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111422

Other (OTH)

AF:

0.00

AC:

AN:

60188

GnomAD4 genome

Cov.:

Alfa

AF:

0.000444

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:2

Feb 05, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: This c.332G>A variant affects a conserved nucleotide, resulting in amino acid change from Ser to Asn. Although 4/4 in-silico tools predict this variant to be benign, no functional studies have been performed to confirm these predictions. This variant was not found in approximately 92088 control chromosomes including the broad and large populations from ExAC. In literature, the variant has been widely reported as a pathogenic variant found in several patients/families with VHL disease, including somatic occurrences. This p.Ser111 is likely to be a mutational hot-spot where other likely pathogenic variant [such as p.S111R (c.331A>C and c.333C>G), p.S111C, p.S111I, etc.] have also been reported. At least one reputable database classifies the variant as pathogenic. Taken together, this variant has been classified as a Pathogenic. -

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

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Pathogenic:1

Apr 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant disrupts the p.Ser111 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 12114495, 16868829, 22071692, 25562111; Invitae). 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. 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: 223186). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 27527340, 28849724). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 111 of the VHL protein (p.Ser111Asn). -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jun 07, 2013

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S111N mutation (also known as c.332G>A) is located in exon 1 of the VHL gene. This alteration results from a G to A substitution at nucleotide position 332. The serine at codon 111 is replaced by asparagine, an amino acid with similar properties. This mutation has been reported in many VHL families affected with retinal angiomas, CNS hemangioblastomas, and renal cell carcinoma. None of the families in the literature had a history of pheochromocytomas which would fit the clinical description of VHL Type 1 (Chen et al. Human Mutation. 1995. 5:66-75; Maher et al. J Med Genet. 1996: 33328-332; Zbar et al. Human Mutation. 1996. 8:348-357; Ong et al. Human Mutation. 2007. 28(2):143-149; Zhang et al. J Cancer Res Clin Oncol. 2008. 134:1211-1218). Based on the available evidence, p.S111N is classified as a pathogenic mutation. This mutation has been referred to as p.S182N (c.545G>A) in older literature. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

D;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.012

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.57

T;T

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.4

L;L

PhyloP100

4.0

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.54

Sift

Benign

0.12

.;T

Sift4G

Benign

0.094

T;T

Polyphen

0.14

B;B

Vest4

0.86

MutPred

0.78

Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);

MVP

1.0

MPC

0.31

ClinPred

0.80

GERP RS

3.4

PromoterAI

0.042

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.97

Mutation Taster

=17/83

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