Submissions for variant NM_003242.6(TGFBR2):c.1240G>A (p.Ala414Thr)

dbSNP: rs2125437095

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002380085	SCV002674381	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2017-10-31	criteria provided, single submitter	clinical testing	The p.A414T variant (also known as c.1240G>A), located in coding exon 4 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1240. The alanine at codon 414 is replaced by threonine, an amino acid with similar properties, and is located in a protein kinase domain. This alteration has been reported in individuals with Loeys-Dietz syndrome and in a cohort of individuals with isolated thoracic aortic aneurysm and dissections (TAAD) (Frischmeyer-Guerrerio PA et al. Sci Transl Med, 2013 Jul;5:195ra94; Jondeau G et al. Circ Cardiovasc Genet, 2016 Dec;9:548-558). This alteration was also found to segregate with disease in a proband with familial TAAD and his three affected children, and authors reported that in vitro studies suggested a lack of protein activity (Bee KJ et al. Circ Cardiovasc Genet, 2012 Dec;5:621-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV002380085	SCV003838137	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-02-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002380085	SCV004293435	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 414 of the TGFBR2 protein (p.Ala414Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TGFBR2-related conditions (PMID: 23099432, 23884466; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1758289). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TGFBR2 protein function. This variant disrupts the p.Ala414 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18852674, 27125181; internal data). 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.