Submissions for variant NM_005902.4(SMAD3):c.728G>A (p.Arg243His)

dbSNP: rs863223736

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196916	SCV000250753	uncertain significance	not provided	2023-09-17	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; Identified in an individual with high myopia and aoritic aneurysm who inherited the variant from a reportedly affected parent (Li et al., 2019); This variant is associated with the following publications: (PMID: 31098894)
Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub	RCV000714908	SCV000845662	uncertain significance	Familial aortopathy	2017-09-13	criteria provided, single submitter	clinical testing	SMAD3 c.728G>A: SMAD3 is involved in transcriptional regulation and cell proliferation pathways, and pathogenic variants are associated with Loeys-Dietz syndrome type 3 and Aneurysms-osteoarthritis syndrome (AOS). To the best of our knowledge this variant has not been reported as disease-causing or as a benign polymorphism and has been detected at an extremely low frequency in control populations (1/245912 alleles; gnomAD database). Another clinical laboratory has detected this variant in at least one patient with TAAD, however they also harboured a pathogenic variant in a different disease-related gene (ClinVar variation ID 213761). The p.Arg243 amino acid residue is highly evolutionarily conserved, however missense prediction algorithms do not provide strong support for or against an impact to the protein.
Color Diagnostics, LLC DBA Color Health	RCV001181148	SCV001346242	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-12-19	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the MH2 protein interaction domain of the SMAD3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/245912 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001181148	SCV001567443	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-12-16	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 243 of the SMAD3 protein (p.Arg243His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of SMAD3-related conditions (PMID: 31098894; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as c.143G>A (p.Arg48His). ClinVar contains an entry for this variant (Variation ID: 213761). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SMAD3 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg243 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). 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.
Ambry Genetics	RCV001181148	SCV002669216	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-01-17	criteria provided, single submitter	clinical testing	The p.R243H variant (also known as c.728G>A), located in coding exon 6 of the SMAD3 gene, results from a G to A substitution at nucleotide position 728. The arginine at codon 243 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.