Submissions for variant NM_004612.4(TGFBR1):c.1459C>T (p.Arg487Trp)

dbSNP: rs111426349

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211856	SCV000200566	pathogenic	Loeys-Dietz syndrome; Familial thoracic aortic aneurysm and aortic dissection	2014-08-21	criteria provided, single submitter	clinical testing	The Arg487Trp variant in TGFBR1 has been reported in 4 individuals with clinical features of Loeys-Dietz syndrome (Loeys 2006, Frischmeyer-Guerrerio 2013, LMM u npublished). Additionally, the Arg487Trp variant was reported in 3 individuals w ith familial thoracic aortic aneurysm and dissection (TAAD) and segregated with disease in 13 affected relatives with TAAD from two of these families (Tran-Fadu lu 2009, Aragon-Martin 2013, Dong 2014). This variant was absent from large popu lation studies. Computational prediction tools and conservation analysis suggest that the Arg487Trp variant may impact the protein, though this information is n ot predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
GeneDx	RCV000200764	SCV000250898	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	Observed in multiple unrelated individuals with Loeys-Dietz syndrome, isolated thoracic aortic aneurysm and dissection (TAAD) or aortic disease, and possible Marfan syndrome in the published literature (Loeys et al., 2006; Tran-Fadulu et al., 2009; Dong et al., 2014; Luo et al., 2016; Teixido-Tura et al., 2016; Yang et al., 2016; Zheng et al., 2018; Jani et al., 2020; Li et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); 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: 16928994, 30341550, 24793577, 21815248, 23884466, 26877057, 27611364, 26848186, 27879313, 21358634, 29510914, 30056620, 34456093, 34150014, 30513140, 30787465, 32152251, 34916229, 25110237, 19542084)
Ambry Genetics	RCV000251089	SCV000319363	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-04-25	criteria provided, single submitter	clinical testing	The p.R487W pathogenic mutation (also known as c.1459C>T), located in coding exon 9 of the TGFBR1 gene, results from a C to T substitution at nucleotide position 1459. The arginine at codon 487 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in association with Loeys Dietz syndrome, thoracic aortic aneurysm and dissection, as well as other aortic disease (Loeys BL et al. N. Engl. J. Med., 2006 Aug;355:788-98; Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6; Yang H et al. Sci Rep, 2016 Sep;6:33002; Luo M et al. Clin. Chim. Acta, 2016 May;456:144-148). In addition, this alteration segregated with the disease in a few apparently unrelated families (Tran-Fadulu V et al. J. Med. Genet., 2009 Sep;46:607-13; Dong SB et al. Ann Vasc Surg, 2014 Nov;28:1909-12; Teixidó-Tura G et al. Heart, 2016 Apr;102:626-32). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000251089	SCV000548339	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 487 of the TGFBR1 protein (p.Arg487Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Loeys-Dietz syndrome and thoracic aortic aneurysm and dissections (PMID: 19542084, 23884466, 24793577, 25110237, 27611364). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12526). 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 TGFBR1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg487 amino acid residue in TGFBR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23884466). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763611	SCV000894459	pathogenic	Loeys-Dietz syndrome 1; Multiple self-healing squamous epithelioma	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000200764	SCV000928187	pathogenic	not provided	2019-01-22	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000200764	SCV001449943	pathogenic	not provided	2019-02-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000251089	SCV001736314	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-11-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 478 in the cytoplasmic kinase domain of the TGFBR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported to segregate with thoracic aortic aneurysm and dissections in over ten individuals from two large families (PMID: 19542084, 25110237). This variant has been observed in individuals affected with Loeys-Dietz syndrome (PMID: 16928994, 23884466, 26848186, 26877057), aortopathy (PMID: 27611364) and Marfan syndrome (PMID: 24793577). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg487Gln, is known to be disease-causing, indicating the importance of arginine residue at this position for TGFBR1 protein function (ClinVar variation ID: 12525). Based on the available evidence, this variant is classified as Pathogenic.
MGZ Medical Genetics Center	RCV000013352	SCV002579631	likely pathogenic	Loeys-Dietz syndrome 1	2021-11-24	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000251089	SCV003838912	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-10-04	criteria provided, single submitter	clinical testing
OMIM	RCV000013352	SCV000033599	pathogenic	Loeys-Dietz syndrome 1	2009-09-01	no assertion criteria provided	literature only