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

dbSNP: rs104893811

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199227	SCV000250946	pathogenic	not provided	2022-02-10	criteria provided, single submitter	clinical testing	Reported in multiple individuals with familial thoracic aortic aneurysm and dissection (TAAD) and in individuals who met diagnostic criteria for Marfan syndrome (Pannu et al., 2005; Singh et al., 2006; Tran-Fadulu et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies and 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).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21267002, 25644172, 19159394, 16251899, 27508510, 16799921, 23685554, 23276923, 28152038, 16027248, 19542084, 21098638)
Ambry Genetics	RCV000252297	SCV000318324	pathogenic	Cardiovascular phenotype	2013-02-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654788	SCV000776687	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 460 of the TGFBR2 protein (p.Arg460Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TGFBR2-related disease (PMID: 16027248, 16799921, 19159394, 19542084). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12514). 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 TGFBR2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGFBR2 function (PMID: 21098638). This variant disrupts the p.Arg460 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16027248, 16251899, 21267002, 25644172, 27508510; Invitae). 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.
All of Us Research Program, National Institutes of Health	RCV000013339	SCV004839378	pathogenic	Loeys-Dietz syndrome 2	2023-11-28	criteria provided, single submitter	clinical testing	This variant has been reported in multiple individuals with thoracic aortic aneurysm and dissection (TAAD), and it has been reported to co-segregate with TAAD in multiple families (PMID: 16799921, 16027248, 19159394, 19542084). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). It is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 21098638). A different missense substitution at this amino acid residue, p.Arg460His, has been previously reported in individuals with TAAD and Loeys-Dietz syndrome, and it is classified as pathogenic (ClinVar variation ID 12515), which supports the functional importance of this position.
OMIM	RCV000013339	SCV000033586	pathogenic	Loeys-Dietz syndrome 2	2005-07-26	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000199227	SCV001808087	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000199227	SCV001967803	likely pathogenic	not provided		no assertion criteria provided	clinical testing