ClinVar Miner

Submissions for variant NM_005902.4(SMAD3):c.1A>C (p.Met1Leu)

dbSNP: rs1555405092
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002315227 SCV000739686 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2018-04-13 criteria provided, single submitter clinical testing The p.M1? variant (also known as c.1A>C), located in coding exon 1 of the SMAD3 gene, results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. An alternate alteration in this codon, c.3G>A, has been reported in a child with hypoplastic left heart syndrome and aortic aneurysm, in his father with osteoarthritis and dilated aortic root, and in the proband's younger brother with no cardiac or osteoarthritis findings at the time of evaluation (Fitzgerald KK et al. Case Rep Genet, 2014 Mar;2014:591516). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV002315227 SCV004368402 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2024-12-10 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SMAD3 mRNA. The next in-frame methionine is located at codon 106. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with spontaneous coronary artery dissection and/or thoracic aortic aneurysm and/or dissection (PMID: 29907982, 33125268; internal data). ClinVar contains an entry for this variant (Variation ID: 520186). This variant disrupts a region of the SMAD3 protein in which other variant(s) (p.Arg74Trp) have been determined to be pathogenic (PMID: 29510914, 31096651; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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