Submissions for variant NM_003242.6(TGFBR2):c.1609C>T (p.Arg537Cys)

dbSNP: rs104893809

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196289	SCV000250956	pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in severe impairment of TGF-beta signaling activity (Mizuguchi et al., 2004; Horbelt et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18827873, 26877057, 20628007, 15235604, 21324918, 21098638, 35753512, 30056620, 33083483, 29543232, 35058154, 27112580, 31915033, 18781618)
Invitae	RCV000529794	SCV000658826	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 537 of the TGFBR2 protein (p.Arg537Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TGFBR2-related diseases (PMID: 15235604, 18781618, 18827873, 21324918, 25116393, 27112580). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12507). 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 TGFBR2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGFBR2 function (PMID: 15235604, 20829218, 21098638). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000196289	SCV000987424	pathogenic	not provided		criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000013331	SCV002025505	likely pathogenic	Loeys-Dietz syndrome 2	2021-03-01	criteria provided, single submitter	research	PM2, PS1
Ambry Genetics	RCV000529794	SCV002703107	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-07-28	criteria provided, single submitter	clinical testing	The p.R537C pathogenic mutation (also known as c.1609C>T), located in coding exon 7 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1609. The arginine at codon 537 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in numerous individuals with thoracic aortic aneurysm and dissection (TAAD) (Mizuguchi T et al. Nat Genet, 2004 Aug;36:855-60; Aalberts JJ et al. Neth Heart J, 2008 Sep;16:299-304; Stheneur C et al. Hum Mutat, 2008 Nov;29:E284-95; Edelman JJ et al. Interact Cardiovasc Thorac Surg, 2011 May;12:863-5; Luo M et al. Clin Chim Acta, 2016 May;456:144-148; Somers AE et al. Am J Med Genet A, 2016 07;170:1786-90; Weerakkody R et al. Genet Med, 2018 11;20:1414-1422; Zheng J et al. Int J Legal Med, 2018 Sep;132:1273-1280; Wang Z et al. Biomed Res Int, 2020 Oct;2020:7857043). Additionally, in vitro assays showed this alteration impacts protein function (Mizuguchi T et al. Nat Genet, 2004 Aug;36:855-60; Horbelt D et al. J Cell Sci, 2010 Dec;123:4340-50). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000013331	SCV003799079	pathogenic	Loeys-Dietz syndrome 2	2022-12-27	criteria provided, single submitter	clinical testing	PS4, PS3, PM5
OMIM	RCV000013331	SCV000033578	pathogenic	Loeys-Dietz syndrome 2	2004-08-01	no assertion criteria provided	literature only
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000529794	SCV000731239	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection		no assertion criteria provided	research