19-52212959-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 4.11

Publications

1 publications found

Variant links:

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]

PPP2R1A Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Houge-Janssens syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, G2P

PPP2R1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 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 VariationId is 916077.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 521503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1A	NM_014225.6 link	c.656C>T	p.Ser219Leu	missense_variant	Exon 6 of 15	ENST00000322088.11	NP_055040.2	P30153A8K7B7
PPP2R1A	NM_001363656.2 link	c.119C>T	p.Ser40Leu	missense_variant	Exon 6 of 15		NP_001350585.1
PPP2R1A	NR_033500.2 link	n.600C>T		non_coding_transcript_exon_variant	Exon 5 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11 link	c.656C>T	p.Ser219Leu	missense_variant	Exon 6 of 15	1	NM_014225.6	ENSP00000324804.6		P30153

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1442742

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716340

African (AFR)

AF:

0.00

AC:

AN:

33116

American (AMR)

AF:

0.00

AC:

AN:

42726

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24402

East Asian (EAS)

AF:

0.00

AC:

AN:

39610

South Asian (SAS)

AF:

0.00

AC:

AN:

82596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102986

Other (OTH)

AF:

0.00

AC:

AN:

59608

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Houge-Janssens syndrome 2

Pathogenic:8

Jan 03, 2022

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 10, 2021

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 16, 2024

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG codes:PS2, PS4, PM2, PP2, PP3 -

Jan 01, 2016

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was identified as de novo (maternity and paternity confirmed). -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2+PS2 -

not provided

Pathogenic:3

Mar 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 15, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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) -

PPP2R1A-related disorder

Pathogenic:1Other:1

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method: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 et al. 2019. PubMed ID: 31531803). Additionally, de novo missense variation is a known mechanism of PPP2R1A-related disease (McRae et al. 2017. PubMed ID: 28135719; Houge et al. 2015. PubMed ID: 26168268). This variant has not been reported in a large population database, indicating this variant is rare. Based on the available evidence, we interpret this variant as pathogenic. -

GenomeConnect - Brain Gene Registry

Significance:not provided

Review Status:no classification provided

Collection Method: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/. -

Inborn genetic diseases

Pathogenic:1

Apr 08, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.090

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Benign

-0.94

MutationAssessor

Pathogenic

3.3

M;.;.

PhyloP100

4.1

PrimateAI

Pathogenic

0.83

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

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.88

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over