rs5030802

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000551.4(VHL):c.208G>A(p.Glu70Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,984 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. E70G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.17

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 16 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain 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 chr3-10142055-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 847948.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

PP5

Variant 3-10142055-G-A is Pathogenic according to our data. Variant chr3-10142055-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142055-G-A is described in Lovd as [Pathogenic]. Variant chr3-10142055-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VHL	NM_000551.4 linkuse as main transcript	c.208G>A	p.Glu70Lys	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2 linkuse as main transcript	c.208G>A	p.Glu70Lys	missense_variant	1/3
VHL	NM_198156.3 linkuse as main transcript	c.208G>A	p.Glu70Lys	missense_variant	1/2
VHL	NR_176335.1 linkuse as main transcript	n.278G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3 linkuse as main transcript	c.208G>A	p.Glu70Lys	missense_variant	1/3	1	NM_000551.4	P1	P40337-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000436

AC:

AN:

229104

Hom.:

AF XY:

0.00000791

AC XY:

AN XY:

126422

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:

0.0000337

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453984

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723244

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:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	Variant summary: VHL c.208G>A (p.Glu70Lys) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 229204 control chromosomes (gnomAD). c.208G>A has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (examples: Hes_2007 and Hwang_2014). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 11, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 01, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15611064]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25078357, 27439424, 36384467, 31087189]. -
Likely pathogenic, criteria provided, single submitter	curation	CIViC knowledgebase, Washington University School of Medicine	-	VHL E70K (c.208G>A) is Likely Pathogenic. E70K missense variant occurs at a very low allele frequency in the general population (0.00001489 allele frequency in ExAC, 4.365e-6 allele frequency in gnomAD) and was previously identified in several unrelated individuals with VHL disease symptoms (see evidence statements). PM1 (6860); PM2 (per above); PP1 (5805); PP4 (5805;6742). -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 70 of the VHL protein (p.Glu70Lys). 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 missense change has been observed in individuals with clinical features of von Hippel-Lindau syndrome (VHL) (PMID: 9829912, 17661816, 19270817, 19408298, 25078357, 25562111, 25715769, 27439424; Invitae). It is commonly reported in individuals of Korean ancestry (PMID: 25078357). ClinVar contains an entry for this variant (Variation ID: 43598). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 15611064). 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

Oct 09, 2017

The p.E70K variant (also known as c.208G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 208. The glutamic acid at codon 70 is replaced by lysine, an amino acid with similar properties. Some studies have proposed this alteration as a Korean hotspot mutation that causes a phenotype consistent with VHL type 1 (Hwang S et al. J. Hum. Genet. 2014 Sep;59(9):488-93; Lee JS et al. BMC Med. Genet. 2016 Jul;17(1):48). It has been identified in many unrelated Korean families with histories of central nervous system and retinal hemangioblastomas (Olschwang S et al. Hum Mut. 1998;12:424; Hes FJ et al. Clin Genet. 2007;72:122; Cho HJ et al. J Korean Med Sci. 2009 Feb;24(1):77-83; Hwang S et al. J. Hum. Genet. 2014 Sep;59(9):488-93; Lee JS et al. BMC Med. Genet. 2016 Jul;17(1):48). It was also seen in a 74-year-old Korean patient with renal clear cell carcinoma and central nervous system hemangioblastomas, as well as a colorectal adenocarcinoma. This patient's two brothers, also presenting with renal cell carcinoma, were positive for the p.E70K alteration (Heo SJ et al. Cancer Res Treat. 2016 Jan;48(1):409-14). In addition, a functional study demonstrated that this alteration led to a modest reduction (20%) in the ability of the VHL protein to bind with the alpha subunit of the hypoxia-inducible transcription factor (HIF) and failure to degrade HIF-2 alpha (Miller F et al. J Biol Chemistry. 2005;280(9):7986). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.067

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.86

D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.8

N;N

REVEL

Pathogenic

0.67

Sift

Benign

0.095

.;T

Sift4G

Benign

0.33

T;T

Polyphen

0.11

B;B

Vest4

0.73

MutPred

0.81

Gain of methylation at E70 (P = 0.0074);Gain of methylation at E70 (P = 0.0074);

MVP

1.0

MPC

0.58

ClinPred

0.57

GERP RS

4.6

Varity_R

0.79

gMVP

0.92

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