Submissions for variant NM_005902.4(SMAD3):c.1118G>A (p.Arg373His)

dbSNP: rs1060500766

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000469242	SCV000543852	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-01-05	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 373 of the SMAD3 protein (p.Arg373His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SMAD3-related conditions (PMID: 25944730, 30661052; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 405561). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMAD3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SMAD3 function (PMID: 16828225). This variant disrupts the p.Arg373 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been observed in individuals with SMAD3-related conditions (PMID: 30661052; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001936	SCV001159707	uncertain significance	Aneurysm-osteoarthritis syndrome	2019-03-16	criteria provided, single submitter	clinical testing	The SMAD3 c.1118G>A; p.Arg373His variant (rs1060500766) is reported in the literature in a single individual affected with aortic dilation/dissection (Wooderchak-Donahue 2015). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported in ClinVar (Variation ID: 405561). The arginine at codon 373 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In cultured cells, this variant exhibits mildly reduced transcriptional activation activity and altered localization in response to TGF-beta treatment (Ku 2007), although it is not certain whether these properties are physiologically relevant. Due to limited information, the clinical significance of the p.Arg373His variant is uncertain at this time. References: Ku JL et al. Genetic alterations of the TGF-beta signaling pathway in colorectal cancer cell lines: a novel mutation in Smad3 associated with the inactivation of TGF-beta-induced transcriptional activation. Cancer Lett. 2007 Mar 18;247(2):283-92. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507884	SCV001713711	likely pathogenic	not provided	2020-07-29	criteria provided, single submitter	clinical testing	PM1, PM2, PS3_Supporting, PP2, PP3, PP1
CeGaT Center for Human Genetics Tuebingen	RCV001507884	SCV001961517	likely pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000469242	SCV002751808	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-11-15	criteria provided, single submitter	clinical testing	The p.R373H variant (also known as c.1118G>A), located in coding exon 8 of the SMAD3 gene, results from a G to A substitution at nucleotide position 1118. The arginine at codon 373 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported 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). Additionally, this alteration was detected in a cancer cell line and suggested to possibly impact TGF-β signaling in in vitro assays, although the physiological relevance is unknown (Ku JL et al. Cancer Lett., 2007 Mar;247:283-92). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000469242	SCV003838411	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-01-14	criteria provided, single submitter	clinical testing