rs397516441

Positions:

• chr3-10149790-A-G
• chr3-10149790-A-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.467A>G​(p.Tyr156Cys) 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. Y156D) 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:6
• Conservation: PhyloP100: 2.85

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 96 pathogenic changes around while only 8 benign (92%) 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, 0.956
• PP5: Variant 3-10149790-A-G is Pathogenic according to our data. Variant chr3-10149790-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 43600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10149790-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.467A>G	p.Tyr156Cys	missense_variant	3/3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.344A>G	p.Tyr115Cys	missense_variant	2/2		NP_937799.1
VHL	NM_001354723.2	c.*21A>G		3_prime_UTR_variant	3/3		NP_001341652.1
VHL	NR_176335.1	n.796A>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.467A>G	p.Tyr156Cys	missense_variant	3/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 13, 2008	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2016	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr156 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 12000816, 19763184), which suggests that this may be a clinically significant amino acid residue. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 19763184). 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: 43600). This missense change has been observed in individuals with pheochromocytoma and/or paraganglioma, likely representing von Hippel-Lindau syndrome type 2C (PMID: 12000816, 16314641, 19029228, 19336503, 20151405; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the VHL protein (p.Tyr156Cys). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2024

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; Published functional studies demonstrate increase in lactate dehydrogenase activity and absence of expression of p53 and TIGAR (PMID: 19763184); This variant is associated with the following publications: (PMID: 23707781, 19958924, 22517557, 20151405, 19576851, 8634692, 19336503, 12000816, 14500403, 19574279, 16314641, 15300849, 18836774, 12807974, 19029228, 24132471, 25825477, 20818339, 30787465, 36715412, 34937752, 29748190, 37529773, 9829912, 19763184, 20660572, 12202531) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2022

The p.Y156C pathogenic mutatio (also known as c.467A>G), located in coding exon 3 of the VHL gene, results from an A to G substitution at nucleotide position 467. The tyrosine at codon 156 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in numerous von Hippel Lindau (VHL) cohorts, predominantly in individuals believed to have VHL type 2C, characterized by familial pheochromocytoma in the absence of other VHL-associated lesions (Amar L et al. J. Clin. Oncol. 2005 Dec; 23(34):8812-8; 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; Gergics P et al. Eur. J. Endocrinol. 2009 Sep; 161(3):495-502; Erlic Z et al. Endocr. Relat. Cancer. 2010 Dec; 17(4):875-83; Gallou C et al. Hum. Mutat. 2004 Sep; 24(3):215-24; Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun; 94(6):1938-44; Kruizinga RC et al. Endocr. Relat. Cancer. 2014 Feb;21:63-71). However, at least one reported proband also had a retinal hemangioblastoma (Dollfus H et al. Invest. Ophthalmol. Vis. Sci. 2002 Sep; 43(9):3067-74), another had a pancreatic neuroendocrine tumor (Erlic Z et al. Endocr. Relat. Cancer. 2010 Dec; 17(4):875-83), and another also had a renal cyst (Kruizinga RC et al. Endocr. Relat. Cancer. 2014 Feb;21:63-71). Based on internal structural analysis, Y156C is deleterious and is mildly destabilizing to the local structure (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well 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	0.85
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.84	T;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.50
MutPred		0.89		Loss of helix (P = 0.0196);.;
MVP		1.0
MPC		1.2
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.84

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: rs397516441; hg19: chr3-10191474; COSMIC: COSV56562896;