NM_000551.4:c.533T>C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000551.4(VHL):c.533T>C(p.Leu178Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.26

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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, 0.992

PP5

Variant 3-10149856-T-C is Pathogenic according to our data. Variant chr3-10149856-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.533T>C	p.Leu178Pro	missense_variant	Exon 3 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_198156.3 link	c.410T>C	p.Leu137Pro	missense_variant	Exon 2 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NM_001354723.2 link	c.*87T>C		3_prime_UTR_variant	Exon 3 of 3		NP_001341652.1
VHL	NR_176335.1 link	n.862T>C		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.533T>C	p.Leu178Pro	missense_variant	Exon 3 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:3

Aug 01, 2018

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 02, 2024

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.533T>C (p.Leu178Pro) variant in the VHL gene is located on the exon 3 and is predicted to replace leucine with proline at codon 178 (p.Leu178Pro). The variant has been reported in multiple unrelated individuals with von Hippel‚ÄìLindau disease and/or pheochromocytoma and segregate with disease (PMID: 31383958, 25867206, 19464396, 8956040, 9452106). An alternative variant disrupting the same amino acid (p.Leu178Arg) has been reported in individuals with Von Hippel-Lindau disease and interpreted as pathogenic (ClinVar ID: 625261). The variant is reported in ClinVar (ID: 428795). The variant is absent in the general population database (gnomAD). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.951). Therefore, the c.533T>C (p.Leu178Pro) variant of VHL has been classified as pathogenic. -

Feb 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.533T>C (p.Leu178Pro) variant in the VHL gene is located on the exon 3 and is predicted to replace leucine with proline at codon 178 (p.Leu178Pro). The variant has been reported in multiple unrelated individuals with von Hippel-Lindau disease and/or pheochromocytoma and segregate with disease (PMID: 31383958, 25867206, 19464396, 8956040, 9452106). An alternative variant disrupting the same amino acid (p.Leu178Arg) has been reported in individuals with Von Hippel-Lindau disease and interpreted as pathogenic (ClinVar ID: 625261). The variant is reported in ClinVar (ID: 428795). The variant is absent in the general population database (gnomAD). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.951). Therefore, the c.533T>C (p.Leu178Pro) variant of VHL has been classified as pathogenic. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Pathogenic:1

Jun 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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: 428795). This variant is also known as 746T>C (p.L249P). This missense change has been observed in individuals with von Hippel-Lindau disease (PMID: 17024664, 19464396, 19763184, 27527340). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 178 of the VHL protein (p.Leu178Pro). -

not provided

Pathogenic:1

Jan 26, 2024

GeneDx

Significance: Likely 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; This variant is associated with the following publications: (PMID: 8634692, 12114495, 7987306, 33415482, 25563310, 18836774, 11058902, 19009041, 19763184, 29748190, 36316043, 35466127, 27527340, 16314641, 14722919, 8956040, 7728151, 10567493, 8707293, 17024664, 7553625, 10408776, 25867206, 19464396, 10761708, 21972040) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Aug 29, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L178P pathogenic mutation (also known as c.533T>C), located in coding exon 3 of the VHL gene, results from a T to C substitution at nucleotide position 533. The leucine at codon 178 is replaced by proline, an amino acid with some similar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with Von Hippel-Lindau syndrome (VHL) both with and without pheochromocytoma (Crossey PA et al. Hum. Mol. Genet. 1994 Aug3(8):1303-8; Erlic et al. Endocrine-Related Cancer. 2010. 17;875-883; Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67(6):758-62; Ong KR et al. Hum. Mutat. 2007 Feb;28(2):143-9; Zbar B et al. Hum. Mutat. 1996;8(4):348-57; Krauss T et al. Endocr Relat Cancer, 2018 09;25:783-793; Bausch B et al. Head Neck, 2016 04;38 Suppl 1:E673-9; Ciotti P et al. Eur J Med Genet May;52:311-4; Ambry internal data). This alteration has also been reported in individuals with personal history of pheochromocytoma or functional paraganglioma but without a formal diagnosis of VHL syndrome (Amar L et al. J. Clin. Oncol. 2005 Dec;23(34):8812-8). In the literature, this alteration has also been referred to as a common VHL germline mutation (Cybulski C et al. J. Med. Genet. 2002 Jul;39(7):E38; López-Guerrero JA et al. Adv Urol 2008:720840). Of note, this alteration is also designated as 746T>C in some published literature. This amino acid position is highly 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

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.4

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.97

Loss of stability (P = 0.0086);.;

MVP

1.0

MPC

1.4

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

gMVP

0.97

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