rs367545984

chr3-10149879-G-Achr3-10149879-G-Cchr3-10149879-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000551.4(VHL):c.556G>A(p.Glu186Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E186D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 7.78

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000551.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VHL	NM_000551.4 linkuse as main transcript	c.556G>A	p.Glu186Lys	missense_variant	3/3	ENST00000256474.3
VHL	NM_198156.3 linkuse as main transcript	c.433G>A	p.Glu145Lys	missense_variant	2/2
VHL	NM_001354723.2 linkuse as main transcript	c.*110G>A		3_prime_UTR_variant	3/3
VHL	NR_176335.1 linkuse as main transcript	n.885G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3 linkuse as main transcript	c.556G>A	p.Glu186Lys	missense_variant	3/3	1	NM_000551.4	P1	P40337-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251418

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000965

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000399

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 04, 2016	Variant summary: Variant affects a conserved nucleotide and result in replacement of a medium size and acidic Glutamic acid (E) with a large size and basic Lysine (K). 3/4 in silico tools predict the variant to be disease causing. It was observed in the Non-Finnish European subcohort of the ExAC project at an allele frequency of 0.003% which exceeds the maximal expected allele frequency of a disease causing VHL variant (0.002). However, the variant was identified in only 2 individuals; therefore the significance of these observations is uncertain. The variant was reported in a Korean family in which the variant carriers presented with Angioma, hemangioblastoma of the brain and renal cell carcinoma (Chen_HumMutat_1995). Additional patients with Type I disease were also reported to carry the variants, however these reports lack information about the prevalence of the variant in healthy individuals, therefore association between the variant and the disease remains uncertain (Stolle_HumMutat_1998, Hwang_JHG_2014, Zbar_HumMutat_1996). HGMD lists variant affecting the same codon c.556G>G (p.E186X) and variants in the close proximity of the variant of interest c.555C>A and c.555C>G (p.Y185X) indicating the variant to be located in a mutational hotspot and suggesting pathogenicity. However, a clinical laboratory classify variant as Uncertain via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant is classified as VUS-possibly pathogenic until more information becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.769G>A, p.E257K; This variant is associated with the following publications: (PMID: 14722919, 8956040, 18836774, 10408776, 9681856, 25637381, 25078357, 20151405, 9829911, 7728151, 28753842, 33102977, Dwivedi2022[Article]) -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 18, 2023	- -

Von Hippel-Lindau syndrome

Uncertain:2

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Dec 31, 2023	- -

Chuvash polycythemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 30, 2023

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 186 of the VHL protein (p.Glu186Lys). This variant is present in population databases (rs367545984, gnomAD 0.01%). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 25078357). This variant is also known as 769G>T(p.Glu186Lys). ClinVar contains an entry for this variant (Variation ID: 161403). 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%. 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2023

The p.E186K variant (also known as c.556G>A), located in coding exon 3 of the VHL gene, results from a G to A substitution at nucleotide position 556. The glutamic acid at codon 186 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in a von Hippel-Lindau (VHL) family affected with retinal angiomas, CNS hemangioblastoma, and renal cell cancer but not pheochromocytomas (Chen F et al. Hum Mutat. 1995;5(1):66-75). This alteration has also been observed in an exome cohort in an unaffected individual (Amendola LM et al. Genome Res. 2015 Mar;25(3):305-15). Of note, this alteration is also known as 769G>A in 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.50

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.76

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.5

N;N

REVEL

Pathogenic

0.81

Sift4G

Uncertain

0.036

D;D

Polyphen

0.99

D;D

Vest4

0.76

MVP

1.0

MPC

0.95

ClinPred

0.86

GERP RS

5.0

Varity_R

0.96

gMVP

0.82

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