Submission Details

The PPP1R12A gene is located on chromosome 12 at 12q21.2-q21.31 and encodes the protein phosphatase 1 regulatory subunit 12A protein. This protein forms part of myosin phosphatase, an enzyme that plays an important regulatory role in cell morphology and motility. PPP1R12A was first reported in relation to autosomal dominant genitourinary and/or brain malformation syndrome in 2020 (Hughes et al., 2020 PMID 31883643). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Twelve unique variants, all of which are predicted to result in protein truncation and nonsense mediated decay, have been reported in humans (Hughes et al., 2020 PMID 31883643). In the majority of cases, the variants were shown to have occurred de novo though parents weren’t available in a few cases. The mechanism for disease is predicted to be haploinsufficiency. This gene-disease relationship is supported by expression in the brain and urogenital system during embryonic development (Hughes et al., 2020 PMID 31883642) and data from C. elegans (Wissman et al., 1999 PMID 10208747), Drosophila (Tan et al., 2003 PMID 12505998), and zebrafish models (Weiser et al., 2009 PMID 19515695). In summary, there is strong evidence to support the relationship between PPP1R12A and autosomal dominant genitourinary and/or brain malformation syndrome. Additional reports in humans published at least three years from the first proposal of the association are needed to reach a definitive classification. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 16Oct2020 (SOP Version 7).