rs730882035

chr3-10149805-G-Achr3-10149805-G-Cchr3-10149805-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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. R161G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.78

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr3-10149804-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 618484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	UniProt
VHL	NM_000551.4	c.482G>A	p.Arg161Gln	missense_variant	3/3	ENST00000256474.3
VHL	NM_198156.3	c.359G>A	p.Arg120Gln	missense_variant	2/2
VHL	NM_001354723.2	c.*36G>A		3_prime_UTR_variant	3/3
VHL	NR_176335.1	n.811G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.482G>A	p.Arg161Gln	missense_variant	3/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461830 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Labs, University Health Network	Feb 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	May 21, 2023	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 22, 2019	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). -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2015	This variant is denoted VHL c.482G>A at the cDNA level and p.Arg161Gln (R161Q) at the protein level. The R161Q pathogenic missense variant in the VHL gene has been reported previously in association with von Hippel Lindau disease (Chen et al., 1995; Shah et al., 2014), and its presence is consistent with the diagnosis in this patient. Functional studies of R161Q shows this variant decreases the interactions responsible for stability of the interdomains creating an open conformation with greater rotation angle and moderately inhibits binding of VHL protein to proline-hydroxylated hypoxia-inducible Factor 1A (HIF1a) peptide (Couve et al., 2014). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2023

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). 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. 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

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	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Pathogenic	0.80
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	D
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

Other links and lift over

dbSNP: rs730882035; hg19: chr3-10191489; COSMIC: COSV56542648;