ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1570G>A (p.Asp524Asn) (rs727504421)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000225734 SCV000250952 pathogenic not provided 2015-04-09 criteria provided, single submitter clinical testing p.Asp524Asn (D524N) GAC>AAC: c.1570 G>A in exon 7 of the TGFBR2 gene (NM_003242.5)The D524N mutation in the TGFBR2 gene has been reported previously in two unrelated individuals with Loeys-Dietz syndrome (Loeys B et al., 2006; Yetman A et al., 2007). D524N results in a semi-conservative amino acid substitution at a position that is conserved across species. A mutation in this residue (D524Y) and mutations in nearby residues (W521R, D522N, P525R, A527T, A527V) in association with a TAAD-related, further supporting the functional importance of this residues and region of the protein. Furthermore, the D524N mutation 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, D524N in the TGFBR2 gene is interpreted as a disease-causing mutation. This variant was found in TAADV2-1
Mendelics RCV000987137 SCV001136357 pathogenic Marfan syndrome 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001042957 SCV001206666 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2019-04-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 524 of the TGFBR2 protein (p.Asp524Asn). 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 to be de novo in an individual affected with clinical features of TGFBR2-related conditions (Invitae) and has been reported in individuals affected with Loeys-Dietz syndrome or ventricular repolarization abnormalities (PMID: 16928994, 17470566, 30158670). ClinVar contains an entry for this variant (Variation ID: 180541). 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 C0). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000157520 SCV000207265 likely pathogenic Loeys-Dietz syndrome 2014-11-25 no assertion criteria provided clinical testing
Institute of Human Genetics, Klinikum rechts der Isar RCV000995668 SCV001149965 pathogenic Loeys-Dietz syndrome 2 2019-10-18 no assertion criteria provided clinical testing

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