ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1336G>A (p.Asp446Asn) (rs886039551)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255277 SCV000322367 pathogenic not provided 2018-10-08 criteria provided, single submitter clinical testing The D446N pathogenic variant in the TGFBR2 gene has been reported previously in multiple unrelated individuals with Loeys Dietz syndrome (Disabelle et al., 2006; Stheneur et al., 2008; Longmuir et al., 2014). The D446N variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D446N variant is a semi-conservative amino acid substitution, occurring at a position that is conserved across species. And, in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, multiple missense variants in nearby residues (E440K, S441F, F442L, Q444K, Y448H, Y448C, and S449F) have been reported in the Human Gene Mutation Database in association with Loeys-Dietz syndrome and Marfan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Given the available information, we interpret D446N as a pathogenic variant.
Invitae RCV000692078 SCV000819885 likely pathogenic Thoracic aortic aneurysm and aortic dissection 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 446 of the TGFBR2 protein (p.Asp446Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with aortic dilation or Loeys-Dietz syndrome including three individuals in whom the variant is reported to be de novo (PMID: 22095581, 19006214, 16251899, 24792536, 23884466, 18781618, 22259224, 21484991). ClinVar contains an entry for this variant (Variation ID: 265447). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). The observation of one or more missense substitutions at this codon (p.Asp446) in affected individuals suggests that this may be a clinically significant residue (PMID: 21484991). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000624602 SCV000740526 likely pathogenic Loeys-Dietz syndrome 1 2016-09-30 criteria provided, single submitter clinical testing

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