ClinVar

Description

This missense variant replaces arginine with tryptophan at codon 74 in the MH1 DNA binding domain of the SMAD3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not alter SMAD3 protein expression levels, but does cause decreased cell survival and lack of downstream target gene expression (PMID: 34434896). This variant has been reported in two individuals affected with Loeys-Dietz syndrome (PMID: 31096651; communication with an external laboratory; ClinVar SCV000825693.5), in an individual affected with familial thoracic aortic dissection and aneurysm (PMID: 29510914), and in an individual affected with isolated thoracic aortic dissection and aneurysm (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg74Gln, is considered to be disease-causing (ClinVar variation ID: 623872), suggesting that arginine at this position is important for SMAD3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.