Submissions for variant NM_014225.6(PPP2R1A):c.656C>T (p.Ser219Leu)

dbSNP: rs1555791268

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000824836	SCV000965730	likely pathogenic	Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome	2016-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000824836	SCV001440102	likely pathogenic	Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome	2021-03-01	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
CeGaT Center for Human Genetics Tuebingen	RCV001531910	SCV001747240	likely pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000824836	SCV001870374	pathogenic	Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome	2024-02-16	criteria provided, single submitter	research	ACMG codes:PS2, PS4, PM2, PP2, PP3
GeneDx	RCV001531910	SCV002028206	pathogenic	not provided	2021-11-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 29100083, 26920370, 31531803)
3billion	RCV000824836	SCV002058466	likely pathogenic	Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome	2022-01-03	criteria provided, single submitter	clinical testing	he variant has been previously reported as de novo in a similarly affected individual (PMID:29100083, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PPP2R1A related disorder (PMID:29100083, PS1_P). A missense variant is a common mechanism associated with Mental retardation (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). TTherefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV001531910	SCV002246436	pathogenic	not provided	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 219 of the PPP2R1A protein (p.Ser219Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PPP2R1A-related conditions (PMID: 29100083, 31531803, 33106617; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 521503). 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 expected to disrupt PPP2R1A protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000824836	SCV002540240	pathogenic	Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome	2021-12-10	criteria provided, single submitter	clinical testing	The PPP2R1A c.656C>T (p.Ser219Leu) missense variant results in the substitution of serine at amino acid position 219 with leucine. This variant has been reported in a de novo heterozygous state in five individuals with PPP2R1A-related neurodevelopmental disorder (Hamdan et al. 2017; Zhang et al. 2020; Lenaerts et al. 2021). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies in HEK293 cells by Lenaerts et al. (2021) demonstrated that the c.656C>T variant showed near complete loss of binding of the B55α and B56β regulatory subunits, while binding to PP2A-C subunit was reduced by about 50%. Based on the available evidence, the c.656C>T (p.Ser219Leu) variant is classified as pathogenic for PPP2R1A-related neurodevelopmental disorder.
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000824836	SCV003918939	pathogenic	Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome	2023-04-20	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003420076	SCV004107322	pathogenic	PPP2R1A-related condition	2023-02-14	criteria provided, single submitter	clinical testing	The PPP2R1A c.656C>T variant is predicted to result in the amino acid substitution p.Ser219Leu. This variant occurred de novo in two patients with developmental and epileptic encephalopathy (Hamdan et al 2017. PubMed ID: 29100083; Zhang Y et al 2019. PubMed ID: 31531803). Additionally, de novo missense variation is a known mechanism of PPP2R1A-related disease (see for example McRae. 2017. PubMed ID: 28135719; Houge. 2015. PubMed ID: 26168268 ). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Based on the available evidence, we interpret this variant as pathogenic.
Ambry Genetics	RCV000623695	SCV000742123	uncertain significance	Inborn genetic diseases	2017-01-18	flagged submission	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000824836	SCV001499946	pathogenic	Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome		no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV003987626	SCV004804566	not provided	PPP2R1A-related disorder		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 01-08-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.