ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1408T>G (p.Tyr470Asp)

dbSNP: rs863224935
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000197170 SCV000255488 likely pathogenic Loeys-Dietz syndrome 2 2013-04-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV002310796 SCV000318668 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2020-02-03 criteria provided, single submitter clinical testing The p.Y470D pathogenic mutation (also known as c.1408T>G), located in coding exon 6 of the TGFBR2 gene, results from a T to G substitution at nucleotide position 1408. The tyrosine at codon 470 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant has been previously reported in an individual with suspected Marfan or Loeys-Dietz syndrome (Lee H et al. JAMA 2014 Nov; 312(18):1880-7) and segregates with disease in one family tested in our laboratory (Ambry internal data). In a study of patients with aortic aneurysms/dissections, an alteration of the same codon, p.Y470S (c.1409A>C), in the protein kinase domain was detected in one patient (Waldmüller S et al. Eur J Cardiothorac Surg. 2007;31(6):970-5). Phosphorylation of p.Y470 has been shown to be important for TGFBR2 function (Chen X et al. J. Clin. Invest. 2014 Aug; 124(8):3295-310), and TGFBR2 is inactivated in a cancer cell line with p.Y470D as well as a second TGFBR2 substitution (p.K52T; Grady WM et al. Cancer Res. 1999 Jan; 59(2):320-4). Based on the supporting evidence, p.Y470D is interpreted as a disease-causing mutation.
Invitae RCV002310796 SCV003482752 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2022-05-21 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr470 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26848186, 27879313; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 217016). This missense change has been observed in individuals with clinical features of Loeys-Dietz syndrome (PMID: 25326637; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 470 of the TGFBR2 protein (p.Tyr470Asp).

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