Submissions for variant NM_003242.6(TGFBR2):c.1489C>T (p.Arg497Ter)

dbSNP: rs863223852

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199072	SCV000250949	likely pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 71 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 18781618, 22113417, 25525159, 17061023, 19996017, 28225382, 29543232, 16799921, 27879313, 27100340)
Ambry Genetics	RCV000244033	SCV000319476	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-08-14	criteria provided, single submitter	clinical testing	The p.R497* pathogenic mutation (also known as c.1489C>T) located in coding exon 6 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1489. This changes the amino acid from an arginine to a stop codon within coding exon 6. This stop codon occurs at the 3' terminus of TGFBR2 and is not expected to trigger nonsense-mediated decay. However, this variant eliminates the last 71 amino acids, including 48 amino acids from the C-terminal end of the protein kinase domain. This alteration has been detected in patients from Loeys-Dietz syndrome (LDS), Marfan syndrome-like, and thoracic aortic aneurysm and dissection (TAAD) cohorts in patients reported to have TAAD and other features consistent with LDS (Singh et al. Hum Mutat. 2006;27(8):770-7; Stheneur C et al. Hum Mutat.2008;29(11):E84-95; Jondeau G et al. Circ Cardiovasc Genet. 2016;9(6):548-558; Weerakkody R et al. Genet. Med. 2018 [Epub ahead of print]). In addition, this mutation has been reported to segregate with disease features in families (Cauldwell M et al. Int J Cardiol. 2016;214:491-2; Tooley MJ et al. Clin Dysmorphol. 2017;26(2):91-94). Multiple nonsense and missense alterations in the C-terminal end of the kinase domain have been associated with LDS or related phenotypes (Loeys BL et al. N Engl J Med. 2006;355:788-98; Stheneur C et al. Hum Mutat. 2008;29:E284-95; Horbelt D et al. J Cell Sci. 2010;123:4340-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000490801	SCV000740527	pathogenic	Loeys-Dietz syndrome 2	2016-12-30	criteria provided, single submitter	clinical testing
Invitae	RCV000244033	SCV000776690	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-12-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TGFBR2 protein in which other variant(s) (p.Gln511*) have been determined to be pathogenic (PMID: 15235604, 18781618). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 213934). This variant is also known as p.R522X. This premature translational stop signal has been observed in individual(s) with aortic dilatation and incomplete Marfan syndrome (PMID: 16799921, 18781618, 28225382; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg497*) in the TGFBR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 71 amino acid(s) of the TGFBR2 protein.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680613	SCV000808043	pathogenic	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449740	SCV001653011	pathogenic	Loeys-Dietz syndrome	2020-05-26	criteria provided, single submitter	clinical testing	The p.Arg497X variant in TGFBR2 has been previously reported in 1 individual with Loeys-Dietz syndrome (LDS) and segregated with disease in at least 6 affected relatives (Tooley 2017). It has also been reported as a de novo occurrence in 1 individual with clinical features of LDS, though it was not clear if maternity and paternity were confirmed (Yang 2012). Additionally, this variant has also been reported in 2 individuals with incomplete Marfan syndrome (Singh et al. 2006, Stheneur et al. 2008). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID# 213934) and is absent from large population studies. This nonsense variant leads to a premature termination codon at position 497. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing 13% of the coding region, with about 72 amino acids removed. Several truncating variants located downstream of the p.Arg497X variant have been described in individuals with TGFBR2-associated disorders (Stheneur 2008, LMM unpublished data). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LDS. ACMG/AMP criteria applied: PM2, PVS1_strong, PP1_Moderate, PM6.
OMIM	RCV000490801	SCV000579392	pathogenic	Loeys-Dietz syndrome 2	2006-08-01	no assertion criteria provided	literature only
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000244033	SCV000731224	pathogenic	Familial thoracic aortic aneurysm and aortic dissection		no assertion criteria provided	research