ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1582C>T (p.Arg528Cys) (rs104893810)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197944 SCV000250954 pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing The R528C pathogenic variant in the TGFBR2 gene has been reported multiple times with LDS, often with early childhood presentation including vascular, craniofacial, and musculoskeletal involvement (Loeys et al., 2005; Loeys et al., 2006; Le Maire et al., 2007; Stheneur et al., 2008; Jamsheer et al., 2009; Chen et al., 2010; Frischmeyer-Guerrerio et al., 2013). Additionally, this variant was reported to occur de novo in multiple families, with confirmation of paternity in at least two families (Loeys et al., 2005; Le Maire et al., 2007; Jamsheer et al., 2009). The R528C variant was also observed to occur apparently de novo in an additional family referred for Marfan Syndrome/TAAD genetic testing at GeneDx. Furthermore, the R528C variant is not observed in large population cohorts (Lek et al., 2016). The R528C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The R528 residue, located in the protein kinase domain, is highly conserved across species, and a variant in the same residue (R528H) has been reported in association with LDS, further supporting the functional importance of this residue (Loeys et al., 2005). Finally, functional studies have shown that the R528C variant results in decreased protein expression and has a dominant-negative effect on TGF-beta induced Smad and ERK signalling (Horbelt et al., 2010).
Invitae RCV000691207 SCV000818955 pathogenic Thoracic aortic aneurysm and aortic dissection 2018-03-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 528 of the TGFBR2 protein (p.Arg528Cys). 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 (ExAC no frequency). This variant has been reported to be de novo in several individuals affected with Loeys–Dietz syndrome (PMID: 15731757, 18781618, 19875893, 20144264). ClinVar contains an entry for this variant (Variation ID: 12512). Experimental studies have shown that this missense change reduces TGFBR2 protein expression and cellular internalization, and impairs the TGF-beta-induced Smad and ERK signaling (PMID: 21098638). A different missense substitution at this codon (p.Arg528His) has been determined to be pathogenic (PMID: 15731757, 18781618, 21098638, 23103230). This suggests that the arginine residue is critical for TGFBR2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000197944 SCV000927232 pathogenic not provided 2017-04-16 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825631 SCV000966988 pathogenic Loeys-Dietz syndrome 2018-02-09 criteria provided, single submitter clinical testing The p.Arg528Cys variant in TGFBR2 has been reported in >5 individuals with Loeys -Dietz syndrome, and occurred de novo in at least 3 of these individuals (Loeys 2005, LeMaire 2007, Stheneur 2008, Frischmeyer-Guerrerio 2013). Additionally, it has also been reported by other clinical laboratories in ClinVar (Variation ID 12512). It was absent from large population studies. In vitro functional studies provide evidence that the p.Arg528Cys variant may impact protein function (Horb elt 2010) and computational prediction tools and conservation analysis suggest t hat the p.Arg528Cys variant may impact the protein. Furthermore, a different pat hogenic variant (p.Arg528His) has been reported in several individuals with Loey s-Dietz syndrome at the same position, supporting this change may not be tolerat ed. In summary, this variant meets criteria to be classified as pathogenic for L oeys-Dietz syndrome in an autosomal dominant manner based upon multiple de novo occurrences, absence from controls, functional and computational evidence and pr esence of another pathogenic variant at the same amino acid position. ACMG/AMP C riteria applied (Richards 2015): PM6_Strong, PM2, PM5, PP3, PS3_Supporting.
OMIM RCV000013337 SCV000033584 pathogenic Loeys-Dietz syndrome 2 2005-03-01 no assertion criteria provided literature only

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