Submissions for variant NM_003242.6(TGFBR2):c.1591G>A (p.Ala531Thr)

dbSNP: rs727503477

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152013	SCV000200581	likely pathogenic	Loeys-Dietz syndrome; Familial thoracic aortic aneurysm and aortic dissection	2014-08-19	criteria provided, single submitter	clinical testing	The Ala531Thr variant in TGFBR2 has been identified by our laboratory in 1 white individual with familial thoracic aortic aneurysm and dissection (familial TAAD ) and segregated with familial TAAD and/or features of Loeys Dietz syndrome in 5 affected relatives including two obligate carriers. It was absent from large po pulation studies. Computational prediction tools and conservation analysis sugge st that the Ala531Thr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although addition al studies are required to fully establish its clinical significance, the Ala531 Thr variant is classified as likely pathogenic based on the segregation data.
Ambry Genetics	RCV002399532	SCV002705732	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-08-02	criteria provided, single submitter	clinical testing	The p.A531T variant (also known as c.1591G>A), located in coding exon 7 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1591. The alanine at codon 531 is replaced by threonine, an amino acid with similar properties, and is located in the kinase domain. This variant has been detected in a cohort suspected of having Marfan syndrome, Loeys-Dietz syndrome (LDS) or thoracic aortic aneurysm and dissection (TAAD), and segregated with TAAD and/or features of LDS in several members of one family (Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6; external lab pers. comm.). This variant has also been detected in additional individuals with TAAD (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Tebben AJ et al. Acta Crystallogr D Struct Biol. 2016 05;72(Pt 5):658-74). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV002508195	SCV002817671	uncertain significance	not provided	2022-06-27	criteria provided, single submitter	clinical testing	Identified in an individual with suspected Loeys-Dietz syndrome and in an individual with spontaneous coronary artery dissection, however segregation and detailed clinical information were not provided in either case (Lerner-Ellis et al., 2014; Saw et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32887874, 24793577)
Invitae	RCV002399532	SCV003525049	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-25	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 165399). This missense change has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 24793577). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 531 of the TGFBR2 protein (p.Ala531Thr).
PreventionGenetics, part of Exact Sciences	RCV003415991	SCV004114409	likely pathogenic	TGFBR2-related condition	2023-07-21	criteria provided, single submitter	clinical testing	The TGFBR2 c.1591G>A variant is predicted to result in the amino acid substitution p.Ala531Thr. This variant was reported in two patients with Loeys-Dietz syndrome (Table S1, Lerner-Ellis. 2014. PubMed ID: 24793577; Saw. 2020. PubMed ID: 32887874). This variant is listed in ClinVar as uncertain and likely pathogenic, and was reported to segregate with TAAD and/or Loeys-Dietz syndrome in six family members undergoing testing in a different laboratory (https://www.ncbi.nlm.nih.gov/clinvar/variation/165399/). This variant is interpreted as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV002399532	SCV004359828	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-09-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 531 of the TGFBR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with thoracic aortic aneurysm and aortic dissection (TAAD) and segregated with TAAD and/or features of Loeys-Dietz syndrome in 5 affected relatives including two obligate carriers (ClinVar submission ID: SCV000200581.5). This variant has also been reported in an additional unrelated individual with Loeys-Dietz syndrome (PMID: 32887874) and in an individual suspected of having TAAD, Loeys-Dietz syndrome or Marfan syndrome (PMID: 24793577). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.