3-10142019-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP6BS1

The NM_000551.4(VHL):c.172C>T(p.Arg58Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000641 in 1,591,366 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R58Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000065 ( 1 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 1.37

Publications

2 publications found

Variant links:

COSMIC-nc: COSV56544159

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: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 34 uncertain in NM_000551.4

BP6

Variant 3-10142019-C-T is Benign according to our data. Variant chr3-10142019-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238102.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000526 (8/152230) while in subpopulation SAS AF = 0.00145 (7/4836). AF 95% confidence interval is 0.000679. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
VHL	NM_000551.4 link	c.172C>T	p.Arg58Trp	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2 link	c.172C>T	p.Arg58Trp	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3 link	c.172C>T	p.Arg58Trp	missense_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1 link	n.242C>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.172C>T	p.Arg58Trp	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000788

AC:

AN:

202942

AF XY:

0.0000984

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000227

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000653

AC:

AN:

1439136

Hom.:

Cov.:

AF XY:

0.0000966

AC XY:

AN XY:

714254

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32984

American (AMR)

AF:

0.00

AC:

AN:

41536

Ashkenazi Jewish (ASJ)

AF:

0.0000390

AC:

AN:

25634

East Asian (EAS)

AF:

0.00

AC:

AN:

38476

South Asian (SAS)

AF:

0.00111

AC:

AN:

83534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102812

Other (OTH)

AF:

0.00

AC:

AN:

59512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000526

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00145

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000506

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Uncertain:2Benign:1

Jun 10, 2023

Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 09, 2024

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

May 18, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Mar 18, 2022

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Aug 09, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Uncertain:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 58 of the VHL protein (p.Arg58Trp). This variant is present in population databases (rs757781272, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 238102). 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 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Mar 07, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24969085) -

Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma

Uncertain:1

Mar 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.

Eigen

Benign

-0.016

Eigen_PC

Benign

-0.088

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

T;T

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Pathogenic

1.2

MutationAssessor

Benign

1.5

L;L

PhyloP100

1.4

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.3

N;N

REVEL

Uncertain

0.50

Sift

Benign

0.055

.;T

Sift4G

Benign

0.070

T;T

Polyphen

0.99

D;D

Vest4

0.27

MutPred

0.57

Loss of methylation at R58 (P = 0.059);Loss of methylation at R58 (P = 0.059);

MVP

1.0

MPC

1.0

ClinPred

0.73

GERP RS

3.7

PromoterAI

-0.096

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.49

gMVP

0.85

Mutation Taster

=89/11

polymorphism

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over