ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.1460G>A (p.Arg487Gln) (rs113605875)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211857 SCV000200567 pathogenic Loeys-Dietz syndrome; Thoracic aortic aneurysm and aortic dissection 2014-08-19 criteria provided, single submitter clinical testing The Arg487Gln variant (TGFBR1) has been reported in the literature in six indivi duals with clinical features of Loeys-Dietz syndrome, with de novo occurrence of the variant confirmed in two of the probands (Loeys 2006, Matyas 2006, Melenovs ky 2008, Yang 2012). In addition, functional analyses revealed that the mutant p rotein alters the normal function of the TGFBR1 protein (Barnett 2011, Goudie 20 11). In summary, this variant meets our criteria to be classified as pathogenic ( based upon de novo occurrence in symptomatic ind ividuals and observed functional effect of the variant.
GeneDx RCV000196834 SCV000250899 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing The R487Q variant in the TGFBR1 gene has been reported in several unrelated individuals with clinical features suggestive of LDS (Matyas et al., 2006; Loeys et al., 2006; Akutsu et al., 2007; Melenovsky et al., 2008; Yang et al., 2012; Wang et al., 2014; Ting et al., 2014). Matyas et al. (2006) reported the R487Q variant as a de novo variant in an individual with TAAD. The R487Q variant was also reported by Loeys et al. (2006) in three unrelated individuals with aortic aneurysm, one of which whom died at 6-months of age from aortic dissection.The R487Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R487Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that the R487Q mutation causes reduced elastin and fibulin 1 expression and impaired deposition of elastic fibers (Barnett et al., 2011). Missense variants in the same residue (R487W, R487P, R487G) have been reported in the Human Gene Mutation Database in association with TGFBR1-related disorders (Stenson et al., 2014), supporting the functional importance of this residue of the protein. In summary, R487Q in the TGFBR1 gene is interpreted as a pathogenic variant.
Invitae RCV000463090 SCV000548337 pathogenic Thoracic aortic aneurysm and aortic dissection 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 487 of the TGFBR1 protein (p.Arg487Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (rs113605875, ExAC no frequency). This variant has been shown to arise de novo in individuals affected with thoracic aortic aneurysms (PMID: 16791849) and has been observed in several unrelated individuals with Loeys-Dietz syndrome (PMID: 18455604, 22113417 and 23884466). ClinVar contains an entry for this variant (Variation ID: 12525). Experimental studies have shown that this missense change causes decreased TGF-beta signaling in vitro (PMID: 21358634). Variants that disrupt the p.Arg487 amino acid residue in TGFBR1 have been observed in affected individuals (PMID: 15731757, 16928994, 22414221, 23884466, 25110237). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc RCV000463090 SCV000782362 pathogenic Thoracic aortic aneurysm and aortic dissection 2016-11-01 criteria provided, single submitter clinical testing
OMIM RCV000013351 SCV000033598 pathogenic Loeys-Dietz syndrome 1 2006-08-01 no assertion criteria provided literature only

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