Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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, |
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 |
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, |
RCV000222953 | SCV000897679 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2018-11-20 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
RCV000222953 | SCV000902149 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2020-03-18 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV000197352 | SCV005414289 | pathogenic | not provided | 2023-11-29 | criteria provided, single submitter | clinical testing | PP2, PP3, PP4, PM2, PM5, PS4 |
Prevention |
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. |