ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1378C>T (p.Arg460Cys) (rs104893811)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199227 SCV000250946 pathogenic not provided 2018-12-05 criteria provided, single submitter clinical testing The R460C pathogenic variant in the TGFBR2 gene has been reported in multiple individuals with familial TAAD and in individuals who met diagnostic criteria for Marfan syndrome (Pannu et al., 2005; Singh et al., 2006; Tran-Fadulu et al., 2009). This variant segregates with disease in more than 15 affected individuals from several families referred for genetic testing at GeneDx and in published literature (Pannu et al., 2005; Singh et al., 2006). Furthermore, R460C is not observed in large population cohorts (Lek et al., 2016). The R460C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, in vitro assays have demonstrated that R460C affects protein trafficking, exhibits a dominant-negative effect, and fails to induce extracellular signal-regulated kinase (ERK) signaling activity (Horbelt et al., 2010). Lastly, other missense variants in the same residue (R460L, R460H) have been reported in HGMD in association with TAAD and Loeys-Dietz syndrome (Stenson et al., 2014), further supporting the functional importance of this residue of the protein.
Ambry Genetics RCV000252297 SCV000318324 pathogenic Cardiovascular phenotype 2013-02-04 criteria provided, single submitter clinical testing
Invitae RCV000654788 SCV000776687 pathogenic Thoracic aortic aneurysm and aortic dissection 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 460 of the TGFBR2 protein (p.Arg460Cys). 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 segregate with TGFBR2-related disease in at least 3 families (PMID: 16027248, 16799921, 19542084, 19159394). ClinVar contains an entry for this variant (Variation ID: 12514). Experimental studies have shown that this missense change affects TGFBR2 protein trafficking and diminishes its signaling activity (PMID: 21098638). Two additional missense substitutions at this codon (p.Arg460His, p.Arg460Leu) have been determined to be pathogenic (PMID: 16027248, 16251899, 25644172, 27508510, 21267002, Invitae). 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.
OMIM RCV000013339 SCV000033586 pathogenic Loeys-Dietz syndrome 2 2005-07-26 no assertion criteria provided literature only

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