ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
30661052 Hostetler et al. (2019) examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of 212 individuals with 51 SMAD3 variants, including more than 10 nonsense, partial gene deletions and frame shift variants, as well as many missense and in-frame variants in MH2 and MH1 domain of the gene. Aortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with SMAD3 MH2 missense variants than those with haploinsufficient variants (42 years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type.
29907982 Overwater et al. (2018) did a targeted NGS analysis of 21 Hereditary Thoracic Aortic Disease (H?TAD) associated genes, including SMAD3 in 810 suspected patients. Out of 66 patients with pathogenic or likely pathogenic variant, 11 patients (11.7%) had SMAD3 variants (3 frame shift, 1 splicing, an in-frame deletion in exon 6 (part of MH2 domain) and a loss of initiation codon). Regarding the in-frame deletion of exon 6 was likely familial since the Proband's father and paternal grandmother were both affected and died in their 30s.
29392890 Schepers et al. (2018) did a case review study of patients with reported and novel SMAD2/3 and TGFB2/3 variants, and summarized diagnostic criteria in the absence of known family history of LDS. Among the novel variants were multiple nonsense, frame shift and splicing variants in SMAD3 gene.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.