rs1057519947

Variant names:

• chr19-52212730-G-A
• rs1057519947
• NM_014225.6:c.548G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-52212730-G-A
• chr19-52212730-G-C
• chr19-52212730-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_014225.6(PPP2R1A):​c.548G>A​(p.Arg183Gln) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R1A NM_014225.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 8.72

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 14 ACMG points.

• PM1: In a region_of_interest SV40 small T antigen binding (size 154) in uniprot entity 2AAA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_014225.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PPP2R1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 4.4565 (above the threshold of 3.09). Trascript score misZ: 5.4176 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 40, Houge-Janssens syndrome 2, complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809
• PP5: Variant 19-52212730-G-A is Pathogenic according to our data. Variant chr19-52212730-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376506.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	c.548G>A	p.Arg183Gln	missense_variant	Exon 5 of 15	ENST00000322088.11	NP_055040.2
PPP2R1A	NM_001363656.2	c.11G>A	p.Arg4Gln	missense_variant	Exon 5 of 15		NP_001350585.1
PPP2R1A	NR_033500.2	n.492G>A		non_coding_transcript_exon_variant	Exon 4 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11	c.548G>A	p.Arg183Gln	missense_variant	Exon 5 of 15	1	NM_014225.6	ENSP00000324804.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Houge-Janssens syndrome 2 Pathogenic:3

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PPP2R1A c.548G>A; p.Arg183Gln variant (rs1057519947; ClinVar Variation ID: 376506) is reported in the literature in multiple individuals affected with clinical findings suggestive of Houge-Janssens syndrome 2 (HJS2; Baker 2022, Gabriel 2022, Wallace 2019, Xing 2022). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.306). This variant is located in the 5th HEAT domain of PPP2R1A critical for binding to the B subunit of PP2A. Functional studies of this variant suggest a dominant negative effect, with evidence of increased tumor growth and hyperphosphorylation of PPA2 signaling substrates GSK, ATK, and mTOR in endometrial cancer cell lines (Haesen 2016). Furthermore, a different missense variant at this codon, p.Arg183Trp, and a nearby codon, p.Arg182Trp, are also considered pathogenic for HJS2 (Lei 2023 and Lenaerts 2021). Based on the available information, the p.Arg183Gln variant is considered pathogenic. References: Baker EK et al. PPP2R1A neurodevelopmental disorder is associated with congenital heart defects. Am J Med Genet A. 2022 Nov;188(11):3262-3277. PMID: 36209351. Gabriel H et al. Trio exome sequencing is highly relevant in prenatal diagnostics. Prenat Diagn. 2022 Jun;42(7):845-851. PMID: 34958143 Haesen D et al. Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth. Cancer Res. 2016 Oct 1;76(19):5719-5731. PMID: 27485451. Lei T et al. Prenatal Diagnosis of PPP2R1A-Related Neurodevelopmental Disorders Using Whole Exome Sequencing: Clinical Report and Review of Literature. Genes (Basel). 2023 Jan 2;14(1):126. PMID: 36672867 Lenaerts L et al. The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction. Genet Med. 2021 Feb;23(2):352-362. PMID: 33106617 Wallace A et al. A Newborn with Severe Ventriculomegaly: Expanding the PPP2R1A Gene Mutation Phenotype. J Pediatr Genet. 2019 Dec;8(4):240-243. PMID: 31687265 Xing Y et al. Prenatal diagnosis for fetuses with isolated and non-isolated congenital heart defects using chromosomal microarray and exome sequencing. Prenat Diagn. 2022 Jun;42(7):873-880. PMID: 35584285. -

not provided Pathogenic:2

Sep 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21381030, 23267135, 21435433, 26619011, 31687265, 35584285, 34958143) -

Mar 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has been observed in individual(s) with clinical features of PPP2R1A-related intellectual disability (PMID: 31687265, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376506). This sequence change replaces arginine with glutamine at codon 183 of the PPP2R1A protein (p.Arg183Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

Intellectual disability Other:1

-

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 10-15-2020 by Lab or GTR ID 26957. Variant found to be mosaic in participant. 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 John Constantino MD PhD 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/. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Pathogenic	4.0	H;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D;.;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.68
MutPred		0.62		Loss of ubiquitination at K188 (P = 0.0716);.;.;
MVP		0.74
MPC		2.8
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.95
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1057519947; hg19: chr19-52715983; COSMIC: COSV59042295; COSMIC: COSV59042295;