Submissions for variant NM_005902.4(SMAD3):c.1268G>A (p.Ser423Asn)

dbSNP: rs1555414503

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521706	SCV000617169	likely pathogenic	not provided	2017-09-15	criteria provided, single submitter	clinical testing	The S423N variant that is likely pathogenic was identified in the SMAD3 gene. It has not been published as pathogenic or been reported as benign to our knowledge. Based on targeted family studies, it has been determined that the S423N variant occurred de novo in an affected individual who underwent TAAD, Marfan syndrome, and Related Disorders genetic testing at GeneDx. The S423N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the S423N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, it occurs at a position that is conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (S423G) has been reported in the Human Gene Mutation Database in association with AOS (Stenson et al., 2014); however, the pathogenicity of this variant has not been definitively determined.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001347590	SCV001541859	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-03-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 423 of the SMAD3 protein (p.Ser423Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Loeys-Dietz syndrome (PMID: 29392890; external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 449264). 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 not expected to disrupt SMAD3 protein function with a negative predictive value of 95%. This variant disrupts the p.Ser423 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been observed in individuals with SMAD3-related conditions (PMID: 30661052, 34122524, 35753512), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV002251486	SCV002522193	likely pathogenic	Aneurysm-osteoarthritis syndrome	2021-08-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001347590	SCV002682593	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-03-02	criteria provided, single submitter	clinical testing	The p.S423N variant (also known as c.1268G>A), located in coding exon 9 of the SMAD3 gene, results from a G to A substitution at nucleotide position 1268. The serine at codon 423 is replaced by asparagine, an amino acid with highly similar properties, and is located in the MH2 domain. This alteration was reported in association with Loeys-Dietz syndrome (Schepers D et al. Hum. Mutat., 2018 05;39:621-634). Other alterations affecting the same amino acid, p.S423R (c.1269T>G) and p.S423G (c.1267A>G), has been reported in association with SMAD3- related disease (Aubart M et al. PLoS ONE, 2014 May;9:e96387; Zhurayev R et al. Genet Res (Camb), 2016 10;98:e13). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002251486	SCV002767609	pathogenic	Aneurysm-osteoarthritis syndrome	2020-07-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Loeys-Dietz syndrome 3. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). This variant is found within the MH2 domain (PMID: 29392890). (SP) 0704 - Other missense variants comparable to the one identified in this case have limited previous evidence for pathogenicity. An alternative missense variant at the same residue (p.Ser423Arg) has been reported as a VUS and observed in a patient with Marfan syndrome, who had an additional variant in FBN1 (ClinVar, PMID: 27724990). Another missense variant (p.Ser423Gly) has been reported as likely pathogenic in two patients with Marfan-like syndrome and Loeys-Dietz syndrome (PMID: 29392890, PMID: 24804794). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo, in two patients with Loeys-Dietz syndrome and thoracic aortic aneurysms and dissections (ClinVar, PMID: 29392890). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign