This variant is classified as a variant of unknown significance because its contribution to autosomal dominant mental retardation with increased head circumference has not been confirmed.
In a patient (COG0681) with autosomal dominant mental retardation with increased head circumference, Loveday et al. (2015) identified a de novo heterozygous in-frame 3-bp deletion (c.468_470delAAC, NM_001161725) in the PPP2R5C gene, resulting in the deletion of residue thr157 (thr157del) in a conserved region in the substrate specificity loop. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was not present among 1,000 population controls or in the ExAC database. Functional studies of the variant were not performed, but Loveday et al. (2015) postulated that the variant could plausibly alter the ability of PP2A to dephosphorylate target substrates and disrupt the PI3K (see 171834)/AKT1 (164730) growth regulatory cascade. The patient was ascertained from a larger cohort of 111 parent-child trios with overgrowth syndrome, often associated with intellectual disability, who underwent exome sequencing. The patient had neonatal hypotonia, febrile seizures, high-arched palate, telecanthus, conductive hearing loss, and mild facial asymmetry.
