Intellectual disabilityGene: PPP2CA Green List (high evidence)
All reported variants in PMID: 30595372 were de novo.
Created: 17 Jul 2019, 3:11 p.m. | Last Modified: 17 Jul 2019, 3:11 p.m.
Panel Version: 0.201
Comment on list classification: Gene status was changed to Green due to a expert review by Konstantinos Varvagiannis. Reynhout et al. (PMID:30595372) reported on 16 individuals with heterozygous pathogenic PPP2CA variants. Frequent features included feeding difficulties, hypotonia, developmental delay (16/16) with intellectual disability. Sufficient individuals to rate Green and phenotype relevant in OMIM and probable in Gene2Phen.
Created: 29 May 2019, 10:52 a.m.
Green List (high evidence)
Reynhout et al. (doi.org/10.1016/j.ajhg.2018.12.002 - PMID not available) report on 16 individuals with heterozygous pathogenic PPP2CA variants.
Frequent features included feeding difficulties, hypotonia, developmental delay (16/16) with intellectual disability (probably 15/16 - a single individual developped cognitive dysfunction following a psychotic episode), language impairment, behavioral problems, seizures (10/16), brain abnormalities and variable other features.
The variants reported included 3 nonsense mutations, 1 frameshift, 1 duplication of one amino acid, 9 missense variants (of which one was observed twice and 2 affected Asp223) as well as a partial gene deletion (spanning also CDKL3).
Various mechanisms seemed to explain the effect of the different variants - among others - haploinsufficiency for some or a dominant negative effect for others, etc.
Type 2A protein phosphatases (PP2As) comprise 3 subunits, a catalytic C-type subunit (PPP2CA encodes the Cα subunit), a scaffolding A-type subunit as well as a regulatory B-type subunit important for their function. Impairment of PP2A-B56δ (encoded by PPP2R5D) binding/functionality was suggested for most of the variants. Similar dysfunction has been observed - among others - upon loss of one functional allele of PPP2R1A.
The effect of 2 variants affecting Asp223 (Asp223Val and Asp233His) was unclear as they largely behaved similar to wild-type in various functional assays. The authors argue that contribution of mutations in other genes could not be ruled out for the individuals harboring these variants, as could also be the case for the subject with disruption of (also) CDKL3.
The authors note overlapping phenotype with PPP2R1A and PPP2R5D-related ID (MIM 616362 and 616355 respectively - genes rated green in this panel).
Brain-specific Ppp2ca knockout in mice (PMID: 29274472) resulted in morphological and behavioral abnormalities partly overlapping with features observed in individuals with PPP2CA mutations. However mice heterozygous for null mutations have not been phenotypically examined (PMID: 30030003).
PPP2CA is not associated with any phenotype in OMIM, nor in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
As a result, PPP2CA can be considered for inclusion in this panel as green.
Created: 28 Dec 2018, 6:55 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Feeding difficulties; Muscular hypotonia; Global developmental delay; Intellectual disability; Language impairment; Seizures; Abnormality of nervous system morphology
Source Expert Review Green was added to PPP2CA. Source Expert Review was added to PPP2CA. Added phenotypes Neurodevelopmental disorder and language delay with or without structural brain abnormalities, 618354 for gene: PPP2CA Publications for gene PPP2CA were changed from 29274472; 30030003 to 29274472; 30030003; 30595372 Rating Changed from No List (delete) to Green List (high evidence)
gene: PPP2CA was added gene: PPP2CA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PPP2CA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PPP2CA were set to 29274472; 30030003 Phenotypes for gene: PPP2CA were set to Feeding difficulties; Muscular hypotonia; Global developmental delay; Intellectual disability; Language impairment; Seizures; Abnormality of nervous system morphology Penetrance for gene: PPP2CA were set to unknown Review for gene: PPP2CA was set to GREEN
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.