rs5030820

chr3-10149822-C-Gchr3-10149822-C-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.499C>G(p.Arg167Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. R167Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.37

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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr3-10149823-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 3-10149822-C-G is Pathogenic according to our data. Variant chr3-10149822-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.499C>G	p.Arg167Gly	missense_variant	3/3	ENST00000256474.3
VHL	NM_198156.3	c.376C>G	p.Arg126Gly	missense_variant	2/2
VHL	NM_001354723.2	c.*53C>G		3_prime_UTR_variant	3/3
VHL	NR_176335.1	n.828C>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.499C>G	p.Arg167Gly	missense_variant	3/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 01, 2018	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 26, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg167 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7987306, 9829912, 21463266, 25563310). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 2219). This variant is also known as 712C>G, p.Arg238Gly. This missense change has been observed in individual(s) with von Hippel–Lindau disease (VHL) or clinical features of VHL (PMID: 7987306, 19574279; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 167 of the VHL protein (p.Arg167Gly). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The p.R167G pathogenic mutation (also known as c.499C>G), located in coding exon 3 of the VHL gene, results from a C to G substitution at nucleotide position 499. The arginine at codon 167 is replaced by glycine, an amino acid with dissimilar properties. This pathogenic mutation has been reported in multiple individual's with clinical features of VHL (Crossey PA et al. Hum Mol Genet. 1994 Aug;3:1303-8; Gergics P et al. Eur J Endocrinol. 2009 Sep;161:495-502; Krauss T et al. Endocr Relat Cancer. 2018 09;25:783-793). Two other alterations at the same codon, p.R167W (c.499C>T) and p.R167Q (c.500G>A), have been described in numerous VHL families (Babinska A et al. Neuro Endocrinol. Lett. 2015 Dec;36:517-20; Lee JS et al. BMC Med. Genet. 2016 Jul;17:48; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175(4):311-23; Chew WHW et al. Mol Genet Genomic Med. 2017 Sep;5(5):602-607; Zbar B et al. Hum. Mutat. 1996;8:348-57; Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67:758-62; Zhou J et al. Pathol. Int. 2010 Jun;60:452-8; Wang X et al. Urology. 2014 Mar;83:675.e1-5; Wong M et al. Chin J Cancer. 2016 Aug;35:79). Available evidence suggests that germline mutations at codon 167 convey an increased risk for developing pheochromocytoma (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3:1303-8; Chen F et al. Hum. Mut. 1995;5:66-75; Zbar B et al. Hum. Mutat. 1996;8:348-57; Olschwang S et al. Hum. Mut. 1998;12:424-30; Fishbein L et al. Ann. Surg. Oncol. 2013 May;20:1444-50). Of note, this variant may be referred to as c.712C>G (p.R238G) in some older 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	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.81
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.96		Gain of relative solvent accessibility (P = 0.0289);.;
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.98
gMVP		0.94

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

Other links and lift over

dbSNP: rs5030820; hg19: chr3-10191506; COSMIC: COSV56545406;