ClinVar

Description

The G74S missense variant in the ACTB gene has been previously published in association with Baraitser-Winter syndrome (DiDonato et al., 2014) and as de novo in the overlapping condition Fryns-Aftimos syndrome (Namiranian et al., 2015), with limited data to fully support pathogenicity. The G74S variant was not observed in approximately 6,500 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 G74S 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (P70L, I75T) have been reported in the Human Gene Mutation Database in association with Baraitser-Winter syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.