Submissions for variant NM_005902.4(SMAD3):c.1117C>T (p.Arg373Cys)

dbSNP: rs863223746

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199856	SCV000250769	uncertain significance	not provided	2023-03-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30661052, 30739908, 33824467)
Invitae	RCV000553894	SCV000658868	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the SMAD3 protein (p.Arg373Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SMAD3-related conditions (PMID: 30661052; Invitae; externalcommunication). ClinVar contains an entry for this variant (Variation ID: 213774). 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. This variant disrupts the p.Arg373 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16828225, 25944730, 30661052; 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.
Color Diagnostics, LLC DBA Color Health	RCV000553894	SCV001358907	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-02-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 373 in the MH2 protein interaction domain of the SMAD3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with thoracic aortic aneurysms and dissections (PMID: 30661052, 30739908) or related conditions (ClinVar SCV000658868.6). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg373His, is known to be pathogenic (Clinvar variation ID: 405561), indicating that arginine at this position is important for SMAD3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374826	SCV001439575	uncertain significance	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Ambry Genetics	RCV000553894	SCV002746733	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-11-15	criteria provided, single submitter	clinical testing	The p.R373C variant (also known as c.1117C>T), located in coding exon 8 of the SMAD3 gene, results from a C to T substitution at nucleotide position 1117. The arginine at codon 373 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a few individuals with thoracic aortic aneurysm (Arnaud P et al. Genet Med, 2019 09;21:2015-2024; Hostetler EM et al. J Med Genet, 2019 04;56:252-260). Another alteration at the same codon, p.R373H (c.1118G>A), has been detected in multiple individuals with thoracic aortic aneurysm, including one individual with additional concerns for a connective tissue disorder (Wooderchak-Donahue W et al. Am J Med Genet A, 2015 Aug;167A:1747-57; Arnaud P et al. Genet Med, 2019 09;21:2015-2024; Hostetler EM et al. J Med Genet, 2019 04;56:252-260; Yang H et al. Orphanet J Rare Dis, 2020 01;15:6; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003640877	SCV004563620	uncertain significance	Aneurysm-osteoarthritis syndrome	2023-11-30	criteria provided, single submitter	clinical testing	The SMAD3 c.1117C>T; p.Arg373Cys variant (rs863223746) is reported in the literature in individuals affected with thoracic aortic aneurysms, dissections, or dilation (Arnaud 2019, Hostetler 2019, Li 2021). This variant is reported in ClinVar (Variation ID: 213774) and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.958). Additionally, another variant at this codon (c.1118G>A, p.Arg373His) has been reported in individuals with aortic dilation/dissection and is considered likely pathogenic (Hostetler 2019, Wooderchak-Donahue 2015). Due to limited information, the clinical significance of the p.Arg373Cys variant is uncertain at this time. References: Arnaud P et al. Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD). Genet Med. 2019 Sep;21(9):2015-2024. PMID: 30739908. Hostetler EM et al. SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium. J Med Genet. 2019 Apr;56(4):252-260. PMID: 30661052. Li Y et al. Evaluating the monogenic contribution and genotype-phenotype correlation in patients with isolated thoracic aortic aneurysm. Eur J Hum Genet. 2021 Jul;29(7):1129-1138. PMID: 33824467. Wooderchak-Donahue W et al. Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. Am J Med Genet A. 2015 Aug;167A(8):1747-57. PMID: 25944730.