Submissions for variant NM_000459.5(TEK):c.2545C>T (p.Arg849Trp)

gnomAD frequency: 0.00001  dbSNP: rs80338908

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810841	SCV001474495	pathogenic	not provided	2020-02-27	criteria provided, single submitter	clinical testing	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.
Institute of Medical and Molecular Genetics, Hospital Universitario La Paz	RCV001705587	SCV001934203	pathogenic	Segmental undergrowth associated with venous malformation without capillary component	2021-04-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001810841	SCV003441334	pathogenic	not provided	2022-11-24	criteria provided, single submitter	clinical testing	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).
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000009876	SCV005049525	pathogenic	Multiple cutaneous and mucosal venous malformations	2024-02-26	criteria provided, single submitter	clinical testing	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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001810841	SCV005198770	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000009876	SCV000030097	pathogenic	Multiple cutaneous and mucosal venous malformations	2010-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000009876	SCV000040678	not provided	Multiple cutaneous and mucosal venous malformations		no assertion provided	literature only
MAGI's Lab - Research, MAGI Group	RCV001327969	SCV001437645	pathogenic	Abnormal cardiovascular system morphology		no assertion criteria provided	provider interpretation
PreventionGenetics, part of Exact Sciences	RCV004754251	SCV005348305	pathogenic	TEK-related disorder	2024-08-16	no assertion criteria provided	clinical testing	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.