2-28783934-A-C
Variant summary
Our verdict is Pathogenic. The variant received 6 ACMG points: 7P and 1B. PS2PP2PM2_SupportingPS4_SupportingBP4
This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586683/MONDO:0021060/128
Frequency
Consequence
NM_002709.3 missense
Scores
Clinical Significance
Conservation
Publications
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 29
GnomAD4 genome
ClinVar
Submissions by phenotype
Noonan syndrome-like disorder with loose anagen hair 2 Pathogenic:2
- -
The p.Glu183Ala variant in the PPP1CB gene occurred de novo in at least 2 individuals with features consistent with PPP1CB-related Noonan syndrome (Hong et al., 2020; Lin et al., 2018; Ma et al., 2016). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The PPP1CB gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that this variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Glu183Ala variant as pathogenic for PPP1CB-related Noonan syndrome in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2_verystrong; PM2; PP2] -
not provided Pathogenic:2
This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 183 of the PPP1CB protein (p.Glu183Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 27681385, 30236064). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 254652). 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 not expected to disrupt PPP1CB protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27681385, 30236064) -
Cardiovascular phenotype Pathogenic:1
The c.548A>C (p.E183A) alteration is located in exon 5 (coding exon 5) of the PPP1CB gene. This alteration results from an A to C substitution at nucleotide position 548, causing the glutamic acid (E) at amino acid position 183 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD), the PPP1CB c.548A>C alteration was not observed, with coverage at this position. This alteration has been previously reported in multiple patients with various phenotypes suggestive of Noonan syndrome including global developmental delay, macrocephaly, seizures, congenital heart defects, and dysmorphic features (Ma, 2016; Lin, 2018; Hong 2020). In addition, another alteration affecting the same amino acid, p.E183V, was reported in a patient with a similar neurodevelopmental disorder (Ma, 2016). The p.E183 amino acid is conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The p.E183A alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
RASopathy Pathogenic:1
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) -
Noonan syndrome-like disorder with loose anagen hair Pathogenic:1
Variant summary: PPP1CB c.548A>C (p.Glu183Ala) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant was absent in 251350 control chromosomes. c.548A>C has been as de novo in individual(s) affected with syndromic Intellectual disability (Lin_2018, and Hong_2020). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30236064, 30236064). ClinVar contains an entry for this variant (Variation ID: 254652). Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at