PPP1CB p.Ala56Pro

The c.166G>C (p.Ala56Pro) variant in PPP1CB is a missense variant predicted to cause substitution of alanine by proline at amino acid 56. This variant is absent from gnomAD v4 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP. The computational predictor REVEL gives a score of 0.463, which is neither above nor below the thresholds predicting a damaging or benign impact on PPP1CB function. This variant has been reported in 1 proband with features of RASopathy (PS4_Supporting; PMID:27264673). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID: 27264673). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS4_P, PM2_P, PP2. (RASopathy VCEP specifications version 1.1; 9/17/2024)