rs200019083

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The ENST00000256474.3(VHL):c.631A>C(p.Met211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,786 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M211I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 1 hom. )

Consequence

VHL
ENST00000256474.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:5

Conservation

PhyloP100: -0.0480

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 311 pathogenic changes around while only 52 benign (86%) in ENST00000256474.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0251773).

BP6

Variant 3-10149954-A-C is Benign according to our data. Variant chr3-10149954-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182990.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=4, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VHL	NM_000551.4 linkuse as main transcript	c.631A>C	p.Met211Leu	missense_variant	3/3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3 linkuse as main transcript	c.508A>C	p.Met170Leu	missense_variant	2/2		NP_937799.1
VHL	NM_001354723.2 linkuse as main transcript	c.*185A>C		3_prime_UTR_variant	3/3		NP_001341652.1
VHL	NR_176335.1 linkuse as main transcript	n.960A>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 linkuse as main transcript	c.631A>C	p.Met211Leu	missense_variant	3/3	1	NM_000551.4	ENSP00000256474	P1	P40337-1
	ENST00000660063.1 linkuse as main transcript			downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250714

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135540

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461490

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000265

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:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000572

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 27, 2024	The VHL c.631A>C (p.Met211Leu) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge, functional studies have not been performed. A VHL-specific in silico multiparametric scoring algorithm indicated that this variant is more likely to be low risk (PMID: 33151962). This variant has been reported in individuals with breast cancer (PMID: 28202063) and renal cell carcinoma (PMID: 31034483). To our knowledge, this variant has not been reported in individuals with Von Hippel-Lindau disease. In summary, the evidence currently available is insufficient to determine the role of this variant in disease. It has therefore been classified as of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 26, 2024	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 20, 2024	This missense variant replaces methionine with leucine at codon 211 of the VHL protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sporadic renal cell carcinoma along with a second VHL variant, c.3G>A, who lacks other manifestations or family history of von Hippel-Lindau syndrome (PMID: 31034483). This variant has been identified in 6/282108 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genomics Labs, University Health Network	Oct 30, 2019	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2018	Variant summary: VHL c.631A>C (p.Met211Leu) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 276540 control chromosomes (gnomAD). The observed variant frequency is approximately 1.2 fold above the estimated maximal expected allele frequency for a pathogenic variant in VHL causing Von Hippel-Lindau Syndrome phenotype (2.1e-05), suggesting that the variant might be benign. The variant, c.631A>C, has been reported in the literature in individuals affected with Breast Cancer (Jalkh_2017). This report does not provide unequivocal conclusions about association of the variant with Von Hippel-Lindau Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x likely benign, 1x uncertain significance). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2021	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25801821, 28202063, 31034483) -

VHL-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

The VHL c.631A>C variant is predicted to result in the amino acid substitution p.Met211Leu. This variant was reported in individuals with renal cell carcinoma or breast cancer (Jalkh et al 2017. PubMed ID: 28202063; Christensen MB et al 2019. PubMed ID: 31034483); however, variants in other genes were also reported. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 211 of the VHL protein (p.Met211Leu). This variant is present in population databases (rs200019083, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer or renal cell carcinoma (PMID: 28202063, 31034483). ClinVar contains an entry for this variant (Variation ID: 182990). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

0.48

DANN

Benign

0.36

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.49

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.025

T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Benign

-0.34

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.12

N;N

REVEL

Uncertain

0.54

Sift

Benign

0.78

.;T

Sift4G

Benign

0.93

T;T

Polyphen

0.0

B;B

Vest4

0.13

MutPred

0.56

Gain of catalytic residue at M211 (P = 0.0928);.;

MVP

0.42

MPC

0.30

ClinPred

0.0048

GERP RS

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.44

gMVP

0.35

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