chr3-10142139-T-C

Variant names:

Variant summary

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

The NM_000551.4(VHL):c.292T>C(p.Tyr98His) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,447,832 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. Y98C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 5.03

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:

Genome browser will be placed here

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 chr3-10142140-A-G is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 3-10142139-T-C is Pathogenic according to our data. Variant chr3-10142139-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142139-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.292T>C	p.Tyr98His	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 link	c.292T>C	p.Tyr98His	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3 link	c.292T>C	p.Tyr98His	missense_variant	Exon 1 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 link	n.362T>C		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 link	c.292T>C	p.Tyr98His	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000134

AC:

AN:

223372

Hom.:

AF XY:

0.0000240

AC XY:

AN XY:

124746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000199

Gnomad OTH exome

AF:

0.000177

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447832

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720736

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:8

Nov 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 03, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr98His variant in VHL has been reported in >25 individuals with Von Hippel-Lindau disease and segregated with disease in >50 affected individuals from several families, and is considered a founder variant in the Black Forest region in Germany (Bender 2001). It has also been identified in 2/100722 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 2223). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Hoffman 2001, Clifford 2001, Shmueli 2013). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Von Hippel- Lindeau disease. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PS3_Supporting, PP3. -

Jan 31, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11483638, 7759077, 34416425, 32869749, 31538058]. Functional studies indicate this variant impacts protein function [PMID: 28052007, 19602254, 16261165, 23840444, 11331612]. This variant is expected to disrupt protein structure [internal Myriad data]. -

Jun 21, 2023

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.292T>C (p.Tyr98His) results in a conservative amino acid change located in the VHL beta/alpha domain (IPR022772) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 223464 control chromosomes in gnomAD. c.292T>C has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome, has been shown to segregate with disease, and has been considered a founder mutation in Black Forest region of Germany (example: Brauch_1995). At least one publication reports experimental evidence evaluating an impact on protein function. One of the most pronounced variant effects results in impaired binding with HIF protein (example: Couve_2014). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 7759077, 25371412). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all submitters have 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

- -

Apr 20, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2019

Clinical Genomics Labs, University Health Network

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Feb 15, 2019

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease. However, available data are from a single family. -

Feb 15, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported as pathogenic in multiple individuals and families with Von Hippel-Lindau disease in the published literature, where it has been shown to segregate with disease (PMIDs: 21204227 (2011), 19763184 (2009), 19336503 (2009), 11709017 (2001), 11483638 (2001), 10567493 (1999), 10408776 (1999), and 7759077 (1995)). Multiple experimental studies indicate that the variant is damaging to VHL protein function (PMIDs: 28643803 (2017), 20855504 (2010), 20388653 (2010), 19620968 (2009), and 16261165 (2006)). Therefore, the variant is classified as pathogenic. -

Mar 23, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

VHL-related disorder

Pathogenic:1

Nov 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The VHL c.292T>C variant is predicted to result in the amino acid substitution p.Tyr98His. This variant has previously been reported in multiple individuals with pheochromocytoma and Von Hippel-Lindau disease (Crossey et al. 1994. PubMed ID: 7987306, described as 505T>C/169Tyr>His; Boedeker et al. 2009. PubMed ID: 19336503; Gallou et al. 1999. PubMed ID: 10408776; Nielsen et al. 2011. PubMed ID: 21204227). This variant is reported in 3 of ~233,000 alleles in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/103904398/). This variant is interpreted as pathogenic. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Pathogenic:1

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 98 of the VHL protein (p.Tyr98His). This variant is present in population databases (rs5030809, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of VHL-related conditions (PMID: 7728151, 7759077, 10408776, 11483638, 19336503, 19763184, 21204227). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2223). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects VHL function (PMID: 10878807, 11331612, 11331613, 12510195, 16261165, 23840444, 25371412). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jun 17, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y98H pathogenic mutation (also known as c.292T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 292. The tyrosine at codon 98 is replaced by histidine, an amino acid with similar properties. This mutation has been reported in numerous VHL families in the literature (Crossey PA et al. Hum Mol Genet. 1994 Aug;3:1303-8; Neumann HP et al. N Engl J Med. 2002 May;346:1459-66; Gallou C et al. Hum. Mutat. 2004 Sep;24:215-24; Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun;94:1938-44; Erlic Z et al. Endocr Relat Cancer. 2010 Dec;17:875-83; Nielsen SM et al. Am J Med Genet A. 2011 Jan;155A:168-73; Klingler JH et al. J Stroke Cerebrovasc Dis. 2013 May;22:437-43; Huang KL et al. Cell. 2018 04;173:355-370.e14; Liu P et al. Gland Surg, 2019 Aug;8:343-353). In addition, this mutation was shown to disrupt microtubule stabilization in vitro and has been noted to be associated with Type 2A VHL (Hergovich A et al. Nat Cell Biol. 2003;5(1):64-70; Bangiyeva V et al. BMC Cancer. 2009;9:229). Of note, this may be referred to as c.505T>A in some literature. Based on available evidence to date, this alteration is considered to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.88

Sift

Benign

0.043

.;D

Sift4G

Pathogenic

0.0

D;T

Polyphen

1.0

D;D

Vest4

0.89

MutPred

0.86

Loss of glycosylation at P103 (P = 0.0211);Loss of glycosylation at P103 (P = 0.0211);

MVP

1.0

MPC

1.2

ClinPred

0.97

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.99

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