Submissions for variant NM_003242.6(TGFBR2):c.1276G>A (p.Ala426Thr) (rs863223849)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197140	SCV000250942	pathogenic	not provided	2013-06-14	criteria provided, single submitter	clinical testing	p.Ala426Thr (GCT>ACT): c.1276 G>A in exon 5 of the TGFBR2 gene (NM_003242.5)The Ala426Thr mutation in the TGFBR2 gene has been reported in association with incomplete Marfan syndrome and related disorders (Stheneur C et al., 2008; Attias D et al., 2009). Stheneur et al. identified Ala426Thr in a male patient with incomplete Marfan syndrome, and bifid uvula, and reported it has occurred de novo in this individual. Ala426Thr results in a non-conservative amino acid substitution of a non-polar Alanine with a polar Threonine at a position that is conserved across species. In silico analysis predicts Ala426Thr is damaging to the protein structure/function. Mutations in nearby residues (Met425Val, Pro427Ser, Pro427Leu) have been reported in association with Marfan syndrome and Loeys-Dietz syndrome, further supporting the functional importance of this region of the protein. Furthermore, Ala426Thr 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.In summary, Ala426Thr in the TGFBR2 gene is interpreted as a disease-causing mutation. This variant was found in TAAD