Variant: NM_002709.3(PPP1CB):c.548A>C (p.Glu183Ala)

CA10586683

254652 (ClinVar)

Gene: PPP1CB

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 5955b408-54e2-4300-87d3-2385f78db691

Approved on: 2024-12-03

Published on: 2025-03-25

HGVS expressions

NM_002709.3:c.548A>C
NM_002709.3(PPP1CB):c.548A>C (p.Glu183Ala)
NC_000002.12:g.28783934A>C
CM000664.2:g.28783934A>C
NC_000002.11:g.29006800A>C
CM000664.1:g.29006800A>C
NC_000002.10:g.28860304A>C
NG_052878.1:g.37187A>C
ENST00000420282.6:c.548A>C
ENST00000427786.2:c.*508A>C
ENST00000441461.6:c.548A>C
ENST00000455580.6:c.464A>C
ENST00000703171.1:c.*595A>C
ENST00000703172.1:c.464A>C
ENST00000703173.1:c.548A>C
ENST00000703174.1:c.671A>C
ENST00000703176.1:c.515A>C
ENST00000703177.1:c.*508A>C
ENST00000703183.1:n.431A>C
ENST00000395366.3:c.548A>C
ENST00000296122.10:c.548A>C
ENST00000358506.6:c.548A>C
ENST00000395366.2:c.548A>C
ENST00000455580.5:c.464A>C
ENST00000462832.5:n.375A>C
NM_002709.2:c.548A>C
NM_206876.1:c.548A>C
NM_206876.2:c.548A>C

Pathogenic

• Met criteria codes: PP2 PS2_Very Strong PM2_Supporting BP4 PS4_Supporting

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PPP1CB Version 1.3.0

Evidence submitted by expert panel

RASopathy VCEP

The c.548A>C (p.Glu183Ala) variant in PPP1CB is a missense variant predicted to cause substitution of glutamate by alanine at amino acid 183. This variant is absent from gnomAD v2 (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. The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP (PP3). The computational predictor REVEL gives a score of 0.283, which is below the threshold of 0.3, does not predict a damaging effect on PPP1CB function (BP4). This variant was observed in a proband with a phenotype consistent with RASopathy (PS4_Supporting; PMID:30236064). This variant has also been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with features of RASopathy (PS2_VeryStrong; PMIDs: 30236064, 27681385). Based on ACMG/AMP criteria, this variant has enough supporting evidence to be classified as uncertain significance; however, the RASopathy VCEP has upgraded this classification to pathogenic based on ClinGen policy. In summary, this variant currently meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VeryStrong, PS4_Supporting, PM2_Supporting, PP2, BP4. (RASopathy VCEP specifications version 1.3; 12/3/2024)

Met criteria codes

• PP2: 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. The missense Z-score in gnomAD V2.1.1 is 4.33 which is above the threshold set by the Rasopathy VCEP
• PS2_Very Strong: This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with features of RASopathy (PS2_VeryStrong; PMIDs: 30236064, 27681385).
• PM2_Supporting: This variant is absent from gnomAD v4
• BP4: The computational predictor REVEL gives a score of 0.283, which is below the threshold of 0.3, does not predict a damaging effect on PPP1CB function
• PS4_Supporting: This variant was observed in a proband with a phenotype consistent with RASopathy.