rs730882035

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000551.4(VHL):c.482G>A(p.Arg161Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,830 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. R161P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.78

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:

ENSG00000287086 (HGNC:):

ENSG00000287086 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a helix (size 11) in uniprot entity VHL_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 3-10149805-G-A is Pathogenic according to our data. Variant chr3-10149805-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 182983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10149805-G-A is described in Lovd as [Pathogenic]. Variant chr3-10149805-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.482G>A	p.Arg161Gln	missense_variant	Exon 3 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_198156.3 link	c.359G>A	p.Arg120Gln	missense_variant	Exon 2 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NM_001354723.2 link	c.*36G>A		3_prime_UTR_variant	Exon 3 of 3		NP_001341652.1
VHL	NR_176335.1 link	n.811G>A		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 link	c.482G>A	p.Arg161Gln	missense_variant	Exon 3 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:4

Aug 18, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VHL c.482G>A (p.Arg161Gln) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, alpha domain (IPR024048) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes. c.482G>A has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (example Chen_1995, Zbar_1996, Stolle_1998, Santarpia_2007, Olschwang_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in disruption of binding to elongin and an unstable VHL protein that is susceptible to proteasomal degradation (Schoenfeld_2000). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as 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

- -

Feb 22, 2017

Clinical Genomics Labs, University Health Network

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 21, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Dec 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: moderately inhibited binding to proline-hydroxylated hypoxia-inducible Factor 1A (HIF1a), increased HIF2a stability and target expression (PMID: 25371412); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.695G>A (p.Arg232Gln); This variant is associated with the following publications: (PMID: 21715564, 29022557, 33219105, 10587522, 14767570, 27539324, 27527340, 29124493, 19135659, 17102087, 28052007, 7728151, 9829912, 8956040, 21362373, 15300849, 9829911, 24466223, 20120764, 9215674, 24707167, 30877234, 31666924, 10900011, 32742360, 33745191, 32561571, 32901917, 30787465, 9497878, 12000816, 23842656, 25371412) -

Mar 22, 2019

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the VHL gene demonstrated a sequence change, c.482G>A, in exon 3 that results in an amino acid change, p.Arg161Gln. This sequence change is absent from large population databases such as ExAC and gnomAD. This pathogenic sequence change has previously been described in multiple patients and families with Von Hippel-Lindau syndrome (Igaki et al., 2018; Zhang et al., 2015; Iada et al., 2004). Functional analyses demonstrated that the p.Arg161Gln change inhibits the VHL protein from binding to proline-hydroxylated hypoxia-inducible factor 1A (HIF1a peptide (Couve et al., 2014). The p.Arg161Gln change affects a highly conserved amino acid residue located in a domain of the VHL protein that is known to be functional. The p.Arg161Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL). -

VHL-related disorder

Pathogenic:1

Sep 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The VHL c.482G>A variant is predicted to result in the amino acid substitution p.Arg161Gln. This variant was reported in numerous individuals with Von Hippel-Lindau syndrome and pheochromocytoma, and has been repeatedly shown to segregate with disease (see for example: Neumann et al. 2002. PubMed ID: 12000816; (described as c.695G>A) Iida et al. 2004. PubMed ID: 14767570; Qi et al. 2013. PubMed ID: 23842656; Couvé et al. 2014. PubMed ID: 25371412; Wong et al. 2016. PubMed ID: 27527340; Pandit et al. 2016. PubMed ID: 27539324; Olschwang et al. 1998. PubMed ID: 9829912). Functional studies suggest this variant decreases the ability of pVHL to bind to its expected substrate, hydroxylated hypoxia inducible factor (HIF-OH), compared to the wild type protein (Couvé et al. 2014. PubMed ID: 25371412). This variant has not been reported in a large population database, indicating this variant is rare. The VHL c.482G>A variant has been classified as pathogenic by numerous labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/). This variant is interpreted as pathogenic. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Pathogenic:1

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 161 of the VHL protein (p.Arg161Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 7728151, 9829911, 12000816, 14767570, 15300849, 20120764, 21362373, 23842656, 24707167). 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.695G>A. ClinVar contains an entry for this variant (Variation ID: 182983). 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%. Experimental studies have shown that this missense change affects VHL function (PMID: 21715564, 25371412). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Dec 07, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R161Q pathogenic mutation (also known as c.482G>A), located in coding exon 3 of the VHL gene, results from a G to A substitution at nucleotide position 482. The arginine at codon 161 is replaced by glutamine, an amino acid with highly similar properties. This well-described mutation has been identified in kindreds with multiple von Hippel Lindau (VHL) tumors including hemangioblastoma, renal cell carcinoma, and pheochromocytoma (PCC), and has also been identified in individuals with isolated PCC (Chen F et al. Hum Mutat. 1995; 5: 66-75; Zbar et al. Hum Mutat. 1996; 8(4): 348-57; Woodward E et al. Hum Mol Genet. 1997; 6(7):1051-6; Olschwang S et al. Hum Mutat. 1998;12(6):424-30; Stolle C et al. Hum Mutat, 1998;12:417-23; Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Santarpia L et al. Ann N Y Acad Sci, 2006 Aug;1073:198-202; Tong A et al. Chin Med Sci J. 2009 Dec;24(4):197-201; Qi XP et al. Mol Med Rep 2013 Sep;8(3):799-805; Crona J et al. PLoS ONE 2014 Jan;9(1):e86756; Shah V et al. Clin Ophthalmol 2014 Mar;8:623-8; Pandit R et al. Eur J Endocrinol, 2016 Oct;175:311-23; Igaki J et al. Clin Pediatr Endocrinol, 2018 Apr;27:87-93; Lomte N et al. Fam Cancer, 2018 07;17:441-449; Dadeviren Çakr A et al. J Clin Res Pediatr Endocrinol, 2018 06;10:179-182; Albattal S et al. Oncotarget, 2019 Oct;10:5919-5931). It has been reported as a de novo finding in two individuals and segregated with disease in several families (Olschwang S et al. Hum Mutat. 1998;12(6):424-30; Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Iida K et al. Int J Mol Med, 2004 Mar;13:401-4; Qi XP et al. Mol Med Rep 2013 Sep;8(3):799-805). Functional studies have shown that p.R161Q disrupts VHL function in hypoxia signaling pathways in vitro (Couvé S et al. Cancer Res. 2014 Nov;74(22):6554-64). Of note, this alteration is also designated as p.R232Q in the 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

0.87

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.6

D;N

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.031

D;D

Polyphen

1.0

D;D

Vest4

0.87

MutPred

0.96

Loss of helix (P = 0.0196);.;

MVP

1.0

MPC

1.1

ClinPred

0.99

GERP RS

4.9

Varity_R

0.97

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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