ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1379G>A (p.Arg460His) (rs104893816)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196002 SCV000250947 pathogenic not provided 2017-01-09 criteria provided, single submitter clinical testing The R460H mutation in the TGFBR2 gene has been reported multiple times in association with Marfan syndrome, TAAD, and related disorders (Pannu H et al., 2005; Disabella E et al., 2006; Law C et al., 2006). Pannu et al. identified R460H in two unrelated families and found this mutation co-segregated with a TAAD phenotype with reduced penetrance. Disabella et al. reported R460H in a 24 year-old female with aortic root dilation who met Ghent criteria for Marfan syndrome. She had a family history of sudden death in her father and paternal aunt (ages 37 and 45, respectively) due to aortic root dissection. Law et al. observed the R460H mutation in one large family with TAAD and a family history of sudden death. Postmortem autopsy on six individuals in this family identified ruptured aortic aneurysm and dissection as the cause of death. Furthermore, R460H was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Mutations at this residue (R460C, R460L) and in nearby residues (M457K, C461Y) have been reported in association with TAAD and other related disorders, supporting the functional importance of this residue and this region of the protein. Moreover, Pannu et al., suggests the R460 residue to be a mutation hot spot" for familial TAAD. Functional studies reported R460H exhibits a dominant-negative effect on extracellular signal-regulated kinase (ERK) and SMAD signaling which leads to a defect in TGF-B signaling (Horbelt D et al., 2010). In summary, R460H in the TGFBR2 gene is interpreted as a disease-causing mutation."
Invitae RCV000702388 SCV000831240 pathogenic Thoracic aortic aneurysm and aortic dissection 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 460 of the TGFBR2 protein (p.Arg460His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with TGFBR2-related conditions in several families and has been found in several independent individuals affected with these conditions (PMID: 16027248, 16885183, 25644172, 27508510, 23884466, 18852674). ClinVar contains an entry for this variant (Variation ID: 12515). Experimental studies have shown that this missense change affects TGFBR2 protein internalization and reduces its signaling activity (PMID: 21098638). This variant disrupts the p.Arg460 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 16027248, 16799921, 19542084, 21098638, 21267002, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013340 SCV000033587 pathogenic Loeys-Dietz syndrome 2 2006-12-01 no assertion criteria provided literature only
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000013340 SCV000854709 pathogenic Loeys-Dietz syndrome 2 2018-06-05 no assertion criteria provided clinical testing

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