Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Center of Genomic medicine, |
RCV001799526 | SCV001739308 | likely pathogenic | Aneurysm-osteoarthritis syndrome | 2020-09-11 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002377898 | SCV002625326 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2023-10-11 | criteria provided, single submitter | clinical testing | The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the SMAD3 gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. This mutation was reported in an individual with thoracic aortic aneurysm and dissection (TAAD) and hypoplastic left heart syndrome; the mutation was also detected in his father, who had osteoarthritis and dilated aortic root, and in his younger brother, who had a history of inguinal hernia but no specific TAAD-related or osteoarthritis findings at the time of evaluation (Fitzgerald KK et al. Case Rep Genet, 2014 Mar;2014:591516). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| All of Us Research Program, |
RCV001799526 | SCV004834580 | pathogenic | Aneurysm-osteoarthritis syndrome | 2024-02-05 | criteria provided, single submitter | clinical testing | This variant alters the translation initiation codon of the SMAD3 mRNA. An alternate in-frame methionine downstream of the initiator methionine occurs at codon 106 in MH1 domain, which is required for DNA binding. Pathogenic missense variants located before codon 106 have been reported (Clinvar), indicating the functional importance of the region that may be affected by this variant. Although functional studies have not been reported, this variant is expected to result in a disrupted protein product and impair SMAD3 protein function. This variant has been reported in two probands affected with aneurysms-osteoarthritis syndrome or hypoplastic left heart syndrome with significant aortic aneurysm and in two affected first-degree family members (PMID: 24711937, 26221609). Different variants that disrupt the initiator codon (c.1A>T, c.1A>C, and c.2T>C) have been observed in individuals affected with thoracic aortic aneurysm and/or dissection, adolescent idiopathic scoliosis or related conditions (PMID: 20851114, 29907982, 33125268, ClinVar SCV001403942.4). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of SMAD3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |