ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1489C>T (p.Arg497Ter) (rs863223852)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199072 SCV000250949 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing The R497X variant in the TGFBR2 gene has been reported in two individuals with incomplete Marfan syndrome and was absent in over 500 control chromosomes (Singh et al., 2006; Stheneur et al., 2008). Singh et al. (2006) identified R497X in a 40 year-old man with no family history who exhibited skeletal findings and a dilated ascending aorta. Stheneur et al. (2008) observed R497X in a 33 year-old man with incomplete marfan syndrome who demonstrated skeletal and cardiac findings. R497X was reported to fully segregate within the family although no additional clinical information or family history information was provided (Stheneur et al., 2008). R497X is predicted to cause loss of normal protein function by protein truncation. Other nonsense and truncation variants in the TGFBR2 gene have been reported in association with Loeys-Dietz or TAAD-related disorders. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics RCV000244033 SCV000319476 pathogenic Thoracic aortic aneurysm and aortic dissection 2015-03-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000490801 SCV000740527 pathogenic Loeys-Dietz syndrome 2 2016-12-30 criteria provided, single submitter clinical testing
Invitae RCV000244033 SCV000776690 pathogenic Thoracic aortic aneurysm and aortic dissection 2018-10-15 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TGFBR2 gene (p.Arg497*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 71 amino acids of the TGFBR2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with aortic dilatation and incomplete Marfan syndrome (PMID: 18781618, 16799921, Invitae) and it has been reported to segregate with Loeys-Dietz syndrome in a single family (PMID: 28225382). ClinVar contains an entry for this variant (Variation ID: 213934). A different truncation (p.Gln511*) that lies downstream of this variant has been determined to be pathogenic (PMID: 18781618, 15235604). This suggests that deletion of this region of the TGFBR2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc RCV000680613 SCV000808043 pathogenic Connective tissue disorder 2018-06-01 criteria provided, single submitter clinical testing
OMIM RCV000490801 SCV000579392 pathogenic Loeys-Dietz syndrome 2 2006-08-01 no assertion criteria provided literature only
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000244033 SCV000731224 pathogenic Thoracic aortic aneurysm and aortic dissection no assertion criteria provided research

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