ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate that R182W affects PP2A holoenzyme formation, and PR72 binding is prevented due to the presence of the R182W mutant protein. Additionally, PP2A phosphatase activity is decreased for the R182W mutant compared to the wild type (Houge et al., 2015).; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25533962, 26168268, 28628100, 28867141, 28135719, 32565546)

This variant was identified as de novo (maternity and paternity confirmed).

This variant has been previously reported as a de novo change in multiple patients with intellectual disability, agenesis of the corpus callosum, and dysmorphic facies (PMID: 25533962, 26168268, 28628100). Cellular binding assays revealed that p.Arg182Trp affected PP2A holoenzyme formation, dephosphorylation dynamics, and link PP2A dysfunction to congenital brain dysfunction (PMID: 26168268). The variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. ClinVar contains an entry for the variant (Variation ID: 190312). The c.544C>T (p.Arg182Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.544C>T (p.Arg182Trp) variant is classified as Pathogenic.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 182 of the PPP2R1A protein (p.Arg182Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability and developmental delay (PMID: 25533962, 26168268). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190312). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PPP2R1A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PPP2R1A function (PMID: 26168268). For these reasons, this variant has been classified as Pathogenic.

The c.544C>T (p.R182W) alteration is located in coding exon 5 of the PPP2R1A gene. This alteration results from a C to T substitution at nucleotide position 544, causing the arginine (R) at amino acid position 182 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD), the PPP2R1A c.544C>T alteration was not observed, with coverage at this position. This alteration has been reported to occur de novo in multiple unrelated patients with a neurodevelopmental disorder. Common clinical findings include developmental delay, lack of ambulation, hypotonia, anomalies of the corpus callosum, and epilepsy (Houge, 2015; Lenaerts, 2020). The p.R182 amino acid is conserved in available vertebrate species. Functional studies demonstrated in vitro that protein with this alteration had defective interaction and binding to other subunits of the PP2A holoenzyme, impairing the formation of PP2A, and decreasing the phosphatase activity of the enzyme (Houge, 2015; Lenaerts, 2020). The in silico prediction for the p.R182W alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

Variant interpreted as Pathogenic and reported on 08-12-2019 by lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.