ClinVar Miner

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

dbSNP: rs863223740
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197352 SCV000250759 likely pathogenic not provided 2021-06-30 criteria provided, single submitter clinical testing Identified in patients with SMAD3-related disorders in published literature (Wooderchak-Donahue et al., 2015; Zarate et al., 2015; Schubert et al., 2016; Camerota et al., 2019; Renner et al., 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Additionally reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 213766; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 27535533, 32352226, 31569402, 30675029, 11779503, 15235019, 20101697, 27135912, 26854089, 22810696, 25944730, 10092624, 23139211, 26133393, 30833837)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000222953 SCV000271265 likely pathogenic Familial 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000222953 SCV000543860 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 268 of the SMAD3 protein (p.Arg268His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SMAD3-related conditions (PMID: 25944730, 26854089; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 213766). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SMAD3 function with a positive predictive value of 95%. This variant disrupts the p.Arg268 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10092624, 29907982; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf RCV000222953 SCV000897679 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2018-11-20 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000222953 SCV000902149 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2020-03-18 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000197352 SCV005414289 pathogenic not provided 2023-11-29 criteria provided, single submitter clinical testing PP2, PP3, PP4, PM2, PM5, PS4
PreventionGenetics, part of Exact Sciences RCV004734851 SCV005361871 pathogenic SMAD3-related disorder 2024-08-06 no assertion criteria provided clinical testing The SMAD3 c.803G>A variant is predicted to result in the amino acid substitution p.Arg268His. This variant has been reported in multiple individuals with hereditary thoracic aortic disease and/or a clinical diagnosis of Loeys-Dietz syndrome (LDS) (Wooderchak-Donahue et al. 2015. PubMed ID: 25944730; Schubert et al. 2016. PubMed ID: 26854089; Renner et al. 2019. PubMed ID: 30675029; Camerota et al. 2019. PubMed ID: 31569402; Mariucci et al. 2020. PubMed ID: 32352226). This variant has also been reported de novo in an individual with LDS and aplastic anemia (Zha et al. 2024. PubMed ID: 38305921). In vitro studies of bone marrow mononuclear cells (BMMNCs) from this patient detected significantly decreased SMAD3 mRNA and protein expression relative to wild type (Zha et al. 2024. PubMed ID: 38305921). This variant has not been reported in the gnomAD database, indicating this variant is rare. Another missense variant at the same amino acid residue (p.Arg268Cys) has been reported in an individual with hereditary thoracic aortic disease and has been shown to be functionally damaging (Stroschein et al. 1999. PubMed ID: 10092624; Overwater et al. 2018. PubMed ID: 29907982). Taken together, the p.Arg268His variant is interpreted as pathogenic.

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