3-10142089-C-T

Position:

chr3-10142089-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_000551.4(VHL):c.242C>T(p.Pro81Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,604,998 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P81S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 2.23

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:

VHL (HGNC:):

VHL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

PP5

Variant 3-10142089-C-T is Pathogenic according to our data. Variant chr3-10142089-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142089-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4 linkuse as main transcript	c.242C>T	p.Pro81Leu	missense_variant	1/3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 linkuse as main transcript	c.242C>T	p.Pro81Leu	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3 linkuse as main transcript	c.242C>T	p.Pro81Leu	missense_variant	1/2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 linkuse as main transcript	n.312C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 linkuse as main transcript	c.242C>T	p.Pro81Leu	missense_variant	1/3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000435

AC:

AN:

229958

Hom.:

AF XY:

0.00

AC XY:

AN XY:

127476

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:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1452832

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723024

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000834

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:5

Likely pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Mar 31, 2021	ACMG classification criteria: PS3, PS4, PM2, PP3 -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Labs, University Health Network	Feb 21, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 03, 2024	This missense variant replaces proline with leucine at codon 81 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with VHL-associated tumor or have a VHL diagnosis (PMID: 17102082, 21389259, 22241717, 24134185, 33219105). This variant has been identified in 1/229958 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2024	Variant summary: VHL c.242C>T (p.Pro81Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 229958 control chromosomes. c.242C>T has been reported in the literature in multiple individuals affected with isolated pheochromocytoma and/or paraganglioma and no other features of von Hippel Lindau syndrome (examples: Castellano_2006, Formenti_2011, Piccini_2012, Kim_2013, Lessi_2014,Dilzell_2016, Kim_2022). 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: 17102082, 21389259, 24134185, 24446253, 22241717, 33219105). ClinVar contains an entry for this variant (Variation ID: 36899). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2024	Observed in individuals with isolated pheochromocytoma and/or paraganglioma and no other features of von Hippel Lindau syndrome (PMID: 17102082, 22241717, 24134185, 33219105; ClinVar); 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; Also known as c.455C>T, p.Pro152Leu, and p.Pro122Leu; This variant is associated with the following publications: (PMID: 24446253, 27730413, 29946849, 22241717, 17102082, 24134185, 21389259, 31589614, 36948667, 35466127, 33219105, 36939592, 34906457, 9829911, 18580449, 18446368, 21463266) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -

Chuvash polycythemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 24, 2023

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the VHL protein (p.Pro81Leu). This variant is present in population databases (rs193922608, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of von Hippel-Lindau disease (type 2C: pheochromocytoma and paraganglioma) (PMID: 17102082, 21389259, 22241717, 24134185, 27730413; Invitae). ClinVar contains an entry for this variant (Variation ID: 36899). 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%. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The p.P81L variant (also known as c.242C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 242. The proline at codon 81 is replaced by leucine, an amino acid with very few similar properties. This alteration has been reported in multiple individuals with diagnoses consistent with of von Hippel-Lindau syndrome (VHL), but not clearly meeting clinical diagnostic criteria; including an individual with a right carotid body paraganglioma (Piccini V et al. Endocr Relat Cancer. 2012 Apr 10;19(2):149-55), a patient with a left para-adrenal paraganglioma (Castellano M et al. Ann N Y Acad Sci. 2006 Aug;1073:156-65), an individual diagnosed with VHL type 2C (Formenti F et al. FASEB J. 2011 Jun;25(6):2001-11), and an individual with pheochromocytoma at age 16 (Kim JH et al. Clin Genet, 2014 Nov;86:482-6). Further, another alteration at this codon, p.P81S (c.241C>T) has been described both as a low-penetrance mutation in VHL type 1 families (Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67:758-62; Glavac D et al. Hum. Genet. 1996 Sep;98:271-80; Hes FJ et al. J. Med. Genet. 2000 Dec;37:939-43; Kondo K et al. Hum. Mol. Genet. 1995 Dec;4:2233-7; Yoshida M et al. Jpn J Cancer Res. 2000 Feb;90:204-212; Zbar B et al. Hum. Mutat. 1996;8:348-57; Alosi D et al. Curr. Genomics. 2017 Feb;18:93-103) and as a nonpathogenic alteration (Erlic Z et al. J Clin Endocrinol Metab. 2010 Jan;95:308-13). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, individuals may not present with classic von Hippel-Lindau syndrome. Clinical correlation is advised. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

L;L

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.3

D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0090

.;D

Sift4G

Benign

0.51

T;D

Polyphen

1.0

D;D

Vest4

0.40

MutPred

0.69

Loss of disorder (P = 0.0251);Loss of disorder (P = 0.0251);

MVP

1.0

MPC

1.0

ClinPred

0.99

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.86

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

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