ClinVar Miner

Submissions for variant NM_005902.4(SMAD3):c.803G>A (p.Arg268His) (rs863223740)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000222953 SCV000902149 likely pathogenic Thoracic aortic aneurysm and aortic dissection 2016-05-20 criteria provided, single submitter clinical testing
GeneDx RCV000197352 SCV000250759 uncertain significance not provided 2018-03-22 criteria provided, single submitter clinical testing The R268H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R268H variant 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (T261I, P263L) have been reported in the Human Gene Mutation Database in association with aneurysms-osteoarthritis syndrome (Stenson et al., 2009), supporting the functional importance of this region of the protein. Nevertheless, the R268H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Institute of Human Genetics,University Medical Center Hamburg-Eppendorf RCV000222953 SCV000897679 pathogenic Thoracic aortic aneurysm and aortic dissection 2018-11-20 criteria provided, single submitter clinical testing
Invitae RCV000222953 SCV000543860 pathogenic Thoracic aortic aneurysm and aortic dissection 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 268 of the SMAD3 protein (p.Arg268His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with aortic dilation and/or dissection (PMID: 25944730, 26854089, Invitae), and it has been observed to be de novo in an individual with clinical features of SMAD3-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 213766). This variant is located in the MAD homology 2 (MH2) domain that is present in other members of the Smad family of proteins and mediates protein-protein interactions (PMID: 11779503). Another variant at this codon (p.Arg268Cys) has been shown to disrupt protein heteroligomerization (PMID: 10092624). In addition, variants at this position in the paralog Smad4 (p.Arg361) have been shown to cause juvenile polyposis coli suggesting that p.Arg268 is important for Smad3 function (PMID: 15235019, 20101697). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000222953 SCV000271265 likely pathogenic Thoracic aortic aneurysm and aortic dissection 2015-10-30 criteria provided, single submitter clinical testing The p.Arg268His variant has been reported in 2 adults with aortic dilation and a neurysm and segregated with disease in 1 affected relative (Chung 2013 abstract, Zarate 2015). This variant was absent from large population studies. In vitro f unctional studies provide some evidence that the p.Arg268His variant impacts the levels of intracellular SMAD3 protein, which may have some effect on the downst ream pathway (Chung 2013). However, these types of assays may not accurately rep resent biological function. Computational prediction tools and conservation anal ysis suggest that this variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, although additio nal studies are required to fully establish its clinical significance, the p.Arg 268His variant is likely pathogenic.

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