Submissions for variant NM_005902.4(SMAD3):c.814G>C (p.Gly272Arg)

dbSNP: rs1057524127

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443464	SCV000534622	uncertain significance	not provided	2016-12-12	criteria provided, single submitter	clinical testing	A novel variant of uncertain significance has been identified in the SMAD3 gene. The G272R variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observedin approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. In addition, the G272R variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differin polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that is conservedacross species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.Nonetheless, this variant lacks observation in a significant number of affected individuals, segregation data, andfunctional evidence, all of which would further clarify pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654805	SCV000776705	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-03-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 272 of the SMAD3 protein (p.Gly272Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SMAD3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 391534). 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%. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594061	SCV005086364	likely pathogenic	Aneurysm-osteoarthritis syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function is a known mechanism of disease in this gene and is associated with Loeys-Dietz syndrome 3 (MIM#613795). However, dominant negative is also a proposed mechanism of disease in this gene associated with missense variants in the MH2 domain (PMID: 30661052). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (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) 0600 - Variant is located in the annotated MH2 domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant is considered likely pathogenic and has been identified in two individuals with SMAD3-related conditions (Invitae personal communication). This variant has also been classified as a VUS by a clinical testing laboratory (ClinVar). (I) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in six individuals from three families (VCGS internal data, Invitae personal communication). (SP) 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