rs1064793290

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS2_SupportingBS1

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.4(VHL):c.89G>A (p.Gly30Glu) is a missense variant predicted to cause substitution of Glycine by Glutamic Acid at position 30. This is prior to the second start site at codon 54. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0001073 (10/50204 from Admixed American Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1). In addition, one commercial laboratory reports at least 3 cases over 60+ with no VHL spectrum tumors, and another commercial laboratory reports too many cases over 65+ without VHL spectrum tumors to review (of 35 cases with no VHL spectrum tumors). The VHL VCEP has determined this meets (BS2_Supporting) due to the number of cases, ages and lack of information on full VHL screening/phenotyping. In summary, this variant meets the criteria to be classified as Likely Benign 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/CA16617781/MONDO:0008667/078

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:6B:3

Conservation

PhyloP100: -1.79

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 Likely_benign. Variant got -5 ACMG points.

BS1

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

BS2

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.89G>A	p.Gly30Glu	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 link	c.89G>A	p.Gly30Glu	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3 link	c.89G>A	p.Gly30Glu	missense_variant	Exon 1 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 link	n.159G>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.89G>A	p.Gly30Glu	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000345

AC:

AN:

144804

Hom.:

AF XY:

0.0000259

AC XY:

AN XY:

77182

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000209

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1388210

Hom.:

Cov.:

AF XY:

0.00000878

AC XY:

AN XY:

683154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000642

Gnomad4 AMR exome

AF:

0.000200

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:

0.0000112

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000285

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:6Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Uncertain:2Benign:1

Jun 25, 2024

ClinGen VHL Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The variant NM_000551.4(VHL):c.89G>A (p.Gly30Glu) is a missense variant predicted to cause substitution of Glycine by Glutamic Acid at position 30. This is prior to the second start site at codon 54. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0001073 (10/50204 from Admixed American Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1). In addition, one commercial laboratory reports at least 3 cases over 60+ with no VHL spectrum tumors, and another commercial laboratory reports too many cases over 65+ without VHL spectrum tumors to review (of 35 cases with no VHL spectrum tumors). The VHL VCEP has determined this meets (BS2_Supporting) due to the number of cases, ages and lack of information on full VHL screening/phenotyping. In summary, this variant meets the criteria to be classified as Likely Benign 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). -

Feb 21, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with glutamic acid at codon 30 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with VHL-related disorders in the literature. This variant has been identified in 7/176170 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2Benign:1

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VHL: PM2:Supporting, BP4 -

Jul 20, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

VHL-related disorder

Uncertain:1

Jan 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The VHL c.89G>A variant is predicted to result in the amino acid substitution p.Gly30Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Uncertain:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 30 of the VHL protein (p.Gly30Glu). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 418538). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on VHL protein function. 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. -

Hereditary cancer-predisposing syndrome

Benign:1

Aug 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.36

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.083

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.34

N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.44

N;N

REVEL

Benign

0.24

Sift

Uncertain

0.013

.;D

Sift4G

Uncertain

0.029

D;D

Polyphen

0.0030

B;B

Vest4

0.23

MutPred

0.19

Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);

MVP

0.87

MPC

0.43

ClinPred

0.031

GERP RS

-3.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.077

gMVP

0.69

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