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

dbSNP: rs104893816

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196002	SCV000250947	pathogenic	not provided	2024-02-14	criteria provided, single submitter	clinical testing	Published 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 (PMID: 21098638); 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: 23884466, 27508510, 27879313, 25644172, 16885183, 30675401, 31098894, 16251899, 16027248, 21098638)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702388	SCV000831240	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 460 of the TGFBR2 protein (p.Arg460His). This variant is present in population databases (rs104893816, gnomAD 0.004%). This missense change has been observed in individuals with TGFBR2-related conditions (PMID: 16027248, 16885183, 18852674, 23884466, 25644172, 27508510). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12515). 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, 16799921, 19542084, 21098638, 21267002; 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000702388	SCV001333527	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-01-17	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000013340	SCV001434870	pathogenic	Loeys-Dietz syndrome 2	2019-06-17	criteria provided, single submitter	clinical testing	The c.1454G>A (p.Arg485His) variant in the TGFBR2 gene has been reported in multiple unrelated families affected with Thoracic Aortic Aneurysm and Dissection (PMID 16027248,16251899, 16885183, 25644172) and segregates with disease in some of the families (PMID 16027248, 16885183). In vitro analysis showed this variant results in severely compromised internalization of the TGF-beta RII protein (PMID 21098638). Multiple in silico algorithms predicted this p.Arg485His change to be deleterious. Therefore, this c.1454G>A (p.Arg485His) variant in the TGFBR2 gene is classified as pathogenic.
Ambry Genetics	RCV000702388	SCV002698236	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-11-03	criteria provided, single submitter	clinical testing	The p.R460H variant (also known as c.1379G>A), located in coding exon 5 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1379. The arginine at codon 460 is replaced by histidine, an amino acid with highly similar properties. This variant has been found to segregate in multiple multigenerational families with syndromic and non-syndromic thoracic aortic aneurysm and dissection (TAAD) (Michaowska A et al. Pol Arch Internal Med, 2020 May; Pannu H et al. Circulation, 2005 Jul;112:513-20; Law C et al. J. Med. Genet., 2006 Dec;43:908-16). It has also been reported in several individuals with TAAD (Loeys BL et al. N. Engl. J. Med., 2006 Aug;355:788-98; Jawaid Y et al. Case Rep Cardiol, 2018 Dec;2018:8014820; Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637; Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Disabella E et al. Eur. J. Hum. Genet., 2006 Jan;14:34-8). Experimental studies indicate that this alteration affects TGFBR2 protein internalization and decreases TGFBR2 expression and signaling activity (Horbelt D et al. J. Cell. Sci., 2010 Dec;123:4340-50; Inamoto S et al. Cardiovasc. Res., 2010 Dec;88:520-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000196002	SCV005198779	pathogenic	not provided	2023-02-23	criteria provided, single submitter	clinical testing
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