ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1609C>T (p.Arg537Cys) (rs104893809)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196289 SCV000250956 pathogenic not provided 2017-03-02 criteria provided, single submitter clinical testing The R537C pathogenic variant in the TGFBR2 gene has been reported multiple times in association with Marfan syndrome, Loeys-Dietz syndrome and other TAAD-related disorders (Mizuguchi et al., 2004; Aalberts et al., 2008; Edelman et al., 2011; Luo et al., 2016). Mizuguchi et al. (2004) reported R537C in at least three affected family members, all of whom met Ghent criteria for Marfan syndrome and had aortic root dilatation. Aalberts et al. (2008) identified R537C in two probands; the first was a 21 year-old female with aortic root aneurysm and dilated pulmonary artery. This individual's parents tested negative for the R537C variant and it was therefore assumed to be de novo. The second proband was a 42 year-old male with aortic valve replacement, aortic root aneurysm and bifid uvula whose mother died from Type B aortic dissection (Aalberts et al., 2008). R537C was also identified in four affected family members (Aalberts et al., 2008). Edelman et al. (2011) observed R537C in a 31 year-old male with Type B aortic dissection and a strong family history of aortopathy. The R537C pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R537C results in a non-conservative amino acid substitution of an Arginine residue located in a highly conserved protein kinase domain (Horbelt et al., 2010). Moreover, functional studies by Mizuguchi et al. (2004) demonstrated R537C results in severe impairment of TGF-beta signaling activity. Lastly, other missense variants at the same residue (R537G, R537P) have been reported in the Human Gene Mutation Database in association with Loeys-Dietz syndrome (Stenson et al., 2014).In summary, R537C in the TGFBR2 gene is interpreted as a pathogenic variant.
Invitae RCV000529794 SCV000658826 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2018-08-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 537 of the TGFBR2 protein (p.Arg537Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs104893809, ExAC no frequency). This variant has been reported in many families and individuals affected with TGFBR2-related diseases (PMID: 15235604, 18781618, 18827873, 21324918, 25116393, 27112580). ClinVar contains an entry for this variant (Variation ID: 12507). Experimental studies have shown that this missense, nonsense change has a deleterious effect on TGBFR2 activity (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
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

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