3-10142001-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_000551.4(VHL):c.154G>T(p.Glu52*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,583,062 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 Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

VHL
NM_000551.4 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 0.417

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 Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.154G>T	p.Glu52*	stop_gained	Exon 1 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 link	c.154G>T	p.Glu52*	stop_gained	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3 link	c.154G>T	p.Glu52*	stop_gained	Exon 1 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 link	n.224G>T		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.154G>T	p.Glu52*	stop_gained	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000104

AC:

AN:

191496

Hom.:

AF XY:

0.00000952

AC XY:

AN XY:

105086

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000344

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000839

AC:

AN:

1430820

Hom.:

Cov.:

AF XY:

0.00000564

AC XY:

AN XY:

709086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000250

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:

0.00000911

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000238

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.00000845

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

May 19, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu52X variant in VHL has been reported in at least 1 sporadic case with VHL-associated tumors (Leonardi 2011). It has also been identified in 3/94886 European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs373068386). This nonsense variant leads to a premature termination codon at position 52, which is predicted to lead to a truncated or absent protein. However, two isoforms of the VHL protein are expressed in humans: the full length protein (pVHL30) and a shorter isoform (pVHL19), which is translated from the methionine residue at position 54 of pVHL30 (Robinson 2014). Both isoforms are reported to have tumor suppressor abilities (Blankenship 1999). The p.Glu52X variant would only be expected to impact the pVHL30 isoform, meaning that a functional VHL tumor suppressor (pVHL19) may still be produced. A mouse model lacking the long isoform of VHL did not have overt phenotypes, supporting that loss of pVHL30 may not be sufficient to cause von Hippel-Lindau (VHL) syndrome (Frew 2013). Nevertheless, several studies suggest that the pVHL19 and pVHL30 have unique cellular functions (Frew 2013, Minervini 2015), and loss of the pVHL30 isoform may lead to clinical manifestations. Only two other studies have reported loss of funtion (LoF) variants that impact only the pVHL30 isoform (Olschwang 1998, Fu 2015), and additional data would provide evidence to support the association of "pVHL30 only" LoF variants to VHL syndrome. In summary, while there is some suspicion for a pathogenic role due to its predicted impact, the clinical significance of the p.Glu52X variant is uncertain. -

Jul 20, 2017

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant in a gene for which loss-of-function is a known mechanism of disease; however, a downstream in-frame Methionine residue could serve as an alternate initiator codon which, if utilized, may result in a functional protein (PMID: 9751722, 9671762, 10102622); Observed in individuals with hemangioblastoma, renal cancer, or pancreatic cancer in published literature, but also in several individuals without personal history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx (PMID: 21463266, 28454591, 29978187, 35032816); This variant is associated with the following publications: (PMID: 21463266, 27651169, 26681312, 28526081, 28454591, 28539463, 28873162, 29790589, 28492532, 29978187, 32994724, 10900011, 34566400, 35032816, Gaspar2024[CaseReport], 9751722, 9671762, 10102622, 35150601) -

Von Hippel-Lindau syndrome

Uncertain:2

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 1 of the VHL gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. However, there is a naturally occurring VHL protein isoform that has start of translation at methionine 54 and appears to retain tumor suppressor activity (PMID: 9671762, 9751722, 10102622), which may ameliorate the deleterious effects of this N-terminal frameshift. To our knowledge, functional studies have not been reported for this variant. This variant has been reported three individuals affected with VHL-associated clinical features including one individual affected with central nervous system hemangioblastoma and pancreatic cyst (PMID: 21463266), an individual affected with multiple retinal and cerebellar hemangioblastoma (PMID: 34566400), and an individual affected with renal cell carcinoma (PMID: 28873162). This variant also has been reported in one individual each affected with pancreatic and breast cancer (PMID: 26681312, 28454591), two individuals affected with erythrocytosis (PMID: 27651169, 29790589) and an individual affected with malignant pleural mesothelioma (PMID: 35032816). This variant has been identified in 4/222880 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of VHL function is a known mechanism of disease (clinicalgenome.org). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

May 16, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Chuvash polycythemia

Uncertain:2

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Aug 07, 2018

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VHL c.154G>T (p.Glu52X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Glu55fsX12, p.Gly57fsX75, p.Val62fsX5). The variant allele was found at a frequency of 4.1e-05 in 24438 control chromosomes. c.154G>T has been reported in the literature in an individual with haemangioblastoma of the central nervous system (Leonardi_2011) as well as other cancer phenotypes (Susswein_2015, Mandelker_2017). These data do not allow any conclusion about variant significance. A functional study showed the variant to undergoing proteasome-dependent degradation (Schoenfeld_2000). However, there is some evidence that a second transcript, in which the variant occurs upstream of the start codon, provides sufficient VHL protein-protein interactions and tumor suppressor activity (Iliopoulos_1998, Schoenfeld_1998). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS - possibly pathogenic. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Uncertain:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu52*) in the VHL gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 54 has the potential to rescue this variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with VHL-related conditions (PMID: 26681312, 27651169, 28454591, 34566400). ClinVar contains an entry for this variant (Variation ID: 182982). Several studies have shown that the VHL protein created from a downstream methionine located at codon 54 is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma

Uncertain:1

Jan 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diffuse midline glioma, H3 K27-altered

Uncertain:1

Apr 28, 2022

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Nov 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E52* variant (also known as c.154G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 154. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This alteration was reported in a patient diagnosed with Von Hippel-Lindau syndrome (VHLS) and developed a retinal capillary hemangioblastoma and in an individual with a hemangioblastoma of the central nervous system and a pancreatic cyst/ tumor (Murro V et al. Mol Vis. 2021 Sep;27:542-554; Leonardi E et al. Ann. Hum. Genet. 2011 Jul; 75(4):483-96). It has also been observed in an individual with advanced renal cell carcinoma (Carlo MI et al. JAMA Oncol. 2018 09;4:1228-1235). This alteration has additionally been identified in a cohort of erythrocytosis patients (Camps C et al. Haematologica. 2016 Nov;101:1306-1318). Premature stop codons are typically deleterious in nature; however, an alternate initiation codon exists two residues downstream of this alteration, and is reported to result in a biologically active isoform, known as VHL19 (Iliopoulos O et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Sep; 95(20):11661-6. Schoenfeld A et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Jul; 95(15):8817-22). In addition, this alteration has been seen internally in multiple individuals without classic clinical features of VHLS (Ambry internal data). Since supporting evidence for this variant is conflicting at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.15

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.51

Vest4

0.58

GERP RS

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

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