ClinVar

Description

The I784T variant in the SMC1A gene has been reported previously in association with Cornelia de Lange syndrome (CdLS). Affected individuals reported to date have all been female with a history of intrauterine growth restriction, global developmental delay, hirsutism, and minor facial dysmorphisms suggestive of CdLS (Limongellie et al., 2010; Gervasini et al., 2013; Fieremans et al., 2016). Additional reported features include microcephaly, congenital heart defects, cleft palate, sensorineural hearing loss, frequent respiratory infections, and severe intellectual disability (Limongellie et al., 2010; Gervasini et al., 2013; Fieremans et al., 2016). The I784T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I784T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I784T as a pathogenic variant, which is consistent with the clinical features reported in this individual.