rs1555791268

chr19-52212959-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_014225.6(PPP2R1A):c.656C>T(p.Ser219Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S219P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP2R1A NM_014225.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 4.11

Genes affected

PPP2R1A (HGNC:9302): (protein phosphatase 2 scaffold subunit Aalpha) This gene encodes a constant regulatory subunit of protein phosphatase 2. Protein phosphatase 2 is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. The constant regulatory subunit A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. This gene encodes an alpha isoform of the constant regulatory subunit A. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-52212958-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 916077.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.
• PP2: Missense variant where missense usually causes diseases, PPP2R1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 19-52212959-C-T is Pathogenic according to our data. Variant chr19-52212959-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP2R1A	NM_014225.6	c.656C>T	p.Ser219Leu	missense_variant	6/15	ENST00000322088.11
PPP2R1A	NM_001363656.2	c.119C>T	p.Ser40Leu	missense_variant	6/15
PPP2R1A	NR_033500.2	n.600C>T		non_coding_transcript_exon_variant	5/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP2R1A	ENST00000322088.11	c.656C>T	p.Ser219Leu	missense_variant	6/15	1	NM_014225.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1442742 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Houge-Janssens syndrome 2 Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 01, 2021	This variant was identified as de novo (maternity and paternity confirmed). -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 10, 2021	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. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 16, 2024	ACMG codes:PS2, PS4, PM2, PP2, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jan 01, 2016	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2021	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) -

PPP2R1A-related disorder Pathogenic:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	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/. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 14, 2023	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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2024

The c.656C>T (p.S219L) alteration is located in exon 6 (coding exon 6) of the PPP2R1A gene. This alteration results from a C to T substitution at nucleotide position 656, causing the serine (S) at amino acid position 219 to be replaced by a leucine (L). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with PP2R1A-related neurodevelopmental disorder (Hamdan, 2017; Zhang, 2020; Lenaerts, 2020; DECIPHER v.9.32; Ambry internal data). PP2A binding assays demonstrated altered PP2A B-type subunit binding and decreased C subunit binding and a PP2A activity assay demonstrated significantly reduced PP2A activity (Lenaerts, 2020). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly 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 in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.3	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.8	D;.;.
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.74
MutPred		0.77		Loss of disorder (P = 0.0233);.;.;
MVP		0.77
MPC		2.4
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555791268; hg19: chr19-52716212; COSMIC: COSV59042650; COSMIC: COSV59042650;