rs397516441

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.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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.85

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 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 rank	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.467A>G	p.Tyr156Cys	missense_variant	Exon 3 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_198156.3 link	c.344A>G	p.Tyr115Cys	missense_variant	Exon 2 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NM_001354723.2 link	c.*21A>G		3_prime_UTR_variant	Exon 3 of 3		NP_001341652.1
VHL	NR_176335.1 link	n.796A>G		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.467A>G	p.Tyr156Cys	missense_variant	Exon 3 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:3

Feb 03, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Aug 13, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Pathogenic:1

Sep 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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). ClinVar contains an entry for this variant (Variation ID: 43600). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 19763184). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Jul 15, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 08, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.84

T;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.5

L;.

PrimateAI

Pathogenic

0.84

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

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

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