rs80338908

Positions:

chr9-27206762-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000459.5(TEK):c.2545C>T(p.Arg849Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,884 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TEK
NM_000459.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 1.02

Variant links:

Genes affected

TEK (HGNC:11724): (TEK receptor tyrosine kinase) This gene encodes a receptor that belongs to the protein tyrosine kinase Tie2 family. The encoded protein possesses a unique extracellular region that contains two immunoglobulin-like domains, three epidermal growth factor (EGF)-like domains and three fibronectin type III repeats. The ligand angiopoietin-1 binds to this receptor and mediates a signaling pathway that functions in embryonic vascular development. Mutations in this gene are associated with inherited venous malformations of the skin and mucous membranes. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Feb 2014]

TEK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.752

PP5

Variant 9-27206762-C-T is Pathogenic according to our data. Variant chr9-27206762-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-27206762-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TEK	NM_000459.5 linkuse as main transcript	c.2545C>T	p.Arg849Trp	missense_variant	15/23	ENST00000380036.10	NP_000450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TEK	ENST00000380036.10 linkuse as main transcript	c.2545C>T	p.Arg849Trp	missense_variant	15/23	1	NM_000459.5	ENSP00000369375	P1	Q02763-1
TEK	ENST00000406359.8 linkuse as main transcript	c.2416C>T	p.Arg806Trp	missense_variant	14/22	2		ENSP00000383977		Q02763-2
TEK	ENST00000519097.5 linkuse as main transcript	c.2101C>T	p.Arg701Trp	missense_variant	13/21	2		ENSP00000430686		Q02763-3
TEK	ENST00000615002.4 linkuse as main transcript	c.*1046C>T		3_prime_UTR_variant	15/23	5		ENSP00000480251

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251002

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135652

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727186

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 27, 2020	The TEK c.2545C>T; p.Arg849Trp variant (rs80338908) is reported in the literature segregating with disease in several large families affected with venous malformations (Shu 2012, Vikkula 1996). This variant is reported in ClinVar (Variation ID: 9293), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 849 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses show kinase activation leading to constitutive phosphorylation and suppression of apoptosis (Morris 2005, Vikkula 1996), and in vivo analyses of the variant protein demonstrate venous malformations in zebrafish (Du 2018). Based on available information, this variant is considered to be pathogenic. References: Du Z et al. Transgenic Expression of A Venous Malformation Related Mutation, TIE2-R849W, Significantly Induces Multiple Malformations of Zebrafish. Int J Med Sci. 2018 Feb 12;15(4):385-394. Morris PN et al. Functional analysis of a mutant form of the receptor tyrosine kinase Tie2 causing venous malformations. J Mol Med (Berl). 2005 Jan;83(1):58-63. Shu W et al. Cutaneomucosal venous malformations are linked to the TIE2 mutation in a large Chinese family. Exp Dermatol. 2012 Jun;21(6):456-7. Vikkula M et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell. 1996 Dec 27;87(7):1181-90. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TEK function (PMID: 8980225). 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 not expected to disrupt TEK protein function. ClinVar contains an entry for this variant (Variation ID: 9293). This missense change has been observed in individual(s) with multiple cutaneous and mucosal venous malformations (PMID: 8980225). It has also been observed to segregate with disease in related individuals. 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 sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 849 of the TEK protein (p.Arg849Trp). -

Multiple cutaneous and mucosal venous malformations

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2010	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Feb 26, 2024	The TEK c.2545C>T (p.Arg849Trp) variant was identified at an allelic fraction consistent with somatic origin. This variant has been identified in multiple individuals with venous malformations (Vikkula M et al., PMID: 8980225; Wouters V et al., PMID: 19888299; Paolacci S et al., PMID: 33105631). This variant has been reported in the ClinVar database as a pathogenic variant in both a germline and somatic state by multiple submitters (Clinvar Variation ID: 9293). This variant is only observed on 4/1,613,884 alleles in the general population (gnomAD v.4.0.0), indicating it is not a common variant. The TEK c.2545C>T (p.Arg849Trp) variant resides within the kinase domain of TIE2, an endothelium-specific receptor tyrosine kinase that is a critical functional domain (Shewchuk LM et al., PMID: 11080633). Computational predictors indicate that this variant is damaging, evidence that correlates with impact to TEK function. In support of this prediction, functional studies show that overexpression of full-length receptors with this variant in insect cells result in an increased autophosphorylation activity (Vikkula M et al., PMID: 8980225). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the TEK c.2545C>T (p.Arg849Trp) variant is classified as pathogenic. -

TEK-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2024

The TEK c.2545C>T variant is predicted to result in the amino acid substitution p.Arg849Trp. This variant was reported in at least 60 individuals in at least 10 unrelated families with venous malformation (Vikkula et al. 1996. PubMed ID: 8980225; Wouters et al. 2009. PubMed ID: 19888299). Functional studies show this variant causes increased receptor hyperphosphorylation and inhibits apoptosis (Wouters et al. 2009. PubMed ID: 19888299; Morris et al. 2004. PubMed ID: 15526080). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Segmental undergrowth associated with venous malformation without capillary component

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical and Molecular Genetics, Hospital Universitario La Paz

Apr 06, 2021

- -

Abnormal cardiovascular system morphology

Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

.;D;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.3

.;M;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.012

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.65

MutPred

0.68

.;Loss of disorder (P = 0.0182);.;

MVP

0.77

MPC

0.82

ClinPred

0.99

GERP RS

5.0

Varity_R

0.69

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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