rs863225082

Positions:

• chr6-43007265-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_Moderate PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_006245.4(PPP2R5D):​c.592G>A​(p.Glu198Lys) 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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:30 O:1
• Conservation: PhyloP100: 10.0

Genes affected

PPP2R5D (HGNC:9312): (protein phosphatase 2 regulatory subunit B'delta) The product of this gene belongs to the phosphatase 2A regulatory subunit B family. Protein phosphatase 2A 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 B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a delta isoform of the regulatory subunit B56 subfamily. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PS1: Transcript NM_006245.4 (PPP2R5D) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPP2R5D. . Gene score misZ 3.6476 (greater than the threshold 3.09). Trascript score misZ 4.9069 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, Hogue-Janssens syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 6-43007265-G-A is Pathogenic according to our data. Variant chr6-43007265-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 190286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43007265-G-A is described in Lovd as [Pathogenic]. Variant chr6-43007265-G-A is described in Lovd as [Likely_pathogenic]. Variant chr6-43007265-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R5D	NM_006245.4	c.592G>A	p.Glu198Lys	missense_variant	5/16	ENST00000485511.6	NP_006236.1
PPP2R5D	NM_180976.3	c.496G>A	p.Glu166Lys	missense_variant	5/16		NP_851307.1
PPP2R5D	NM_180977.3	c.274G>A	p.Glu92Lys	missense_variant	3/14		NP_851308.1
PPP2R5D	NM_001270476.2	c.139G>A	p.Glu47Lys	missense_variant	5/16		NP_001257405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R5D	ENST00000485511.6	c.592G>A	p.Glu198Lys	missense_variant	5/16	1	NM_006245.4	ENSP00000417963	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hogue-Janssens syndrome 1 Pathogenic:18 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	May 28, 2018	This variant has been previously reported in the Human Gene Mutation Database (HGMD) and has been described as a recurrent de novo heterozygous change in patients with macrocephaly, developmental delay, hypotonia, and EEG abnormalities (PMID: 26168268, 28554332, 28628100, 25972378, 29296277). The c.592G>A (p.Glu198Lys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Functional analysis of cells expressing the p.Glu298Lys variant showed deficient PP2A holoenzyme formation (PMID: 26168268). This change is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.592G>A (p.Glu198Lys) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	Dec 25, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -
Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Mar 25, 2019	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-03-25 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 11, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 30, 2018	Variant summary: PPP2R5D c.592G>A (p.Glu198Lys) results in a conservative amino acid change (however with charge reversal) in a highly conserved acidic loop that faces and directly interacts with the catalytic subunit of PP2A; and a charge alteration in this acidic surface could potentially interrupt subunit interactions (Houge 2015). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246254 control chromosomes (gnomAD). The variant, c.592G>A, has been reported in the literature as a de novo mutation in multiple individuals affected with Mental retardation, autosomal dominant 35 (MRD35) (Houge 2015, Loveday 2015). These data indicate that the variant is very likely to be associated with disease. At least one of these publications also reported experimental evidence evaluating an impact on protein function, demonstrating loss of binding to the catalytic subunit, which leads to a defect in PP2A-B56delta-dependent dephosphorylation activity (Houge 2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (4x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 07, 2023	_x000D_ Criteria applied: PS2, PS3, PS4_MOD, PM1, PM2_SUP, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	May 22, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (PMID: 26168268, 25972378, PS2 and PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 04, 2023	PS2, PS3, PS4, PM1, PM2, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 11, 2021	The de novo heterozygous c.592G>A (p.Glu198Lys) missense variant identified in the PPP2R5D gene is a known recurrent de novo pathogenic variant and has been reported in multiple unrelated individuals [PMID:28554332; PMID:28191890; PMID: 29296277; PMID: 26168268]. It is the most frequently identified variant in patients affected with PPP2R5D-Related neurodevelopmental disorder [PMID:30676711]. The variant has been reported as Pathogenic in ClinVar database [Variation ID: 190286]. The variant is absent from gnomAD(v3) database suggesting it is not a common benign variant inthe populations represented in that database. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico predictiontools. In vitro functional studies showed that the p.Glu298Lys variant results in deficient PP2A holoenzyme formation [PMID: 26168268]. Based on the available evidence, the de novo heterozygous c.592G>A (p.Glu198Lys) missense variant identified in the PPP2R5D gene is reported as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Dominant negative is a proposed mechanism of disease in this gene and is associated with PPP2R5D-related intellectual disability (MIM#616355). Missense variants in transfected HEK293 cells have demonstrated an inability to assemble into a holoenzyme complex however, co-expression with wildtype protein was not performed. Loss of function is also a potential mechanism (PMID: 32074998, PMID: 26168268). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed as de novo in multiple individuals with intellectual disability, macrocephaly, hypotonia and developmental delay (ClinVar, GeneReviews). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Jun 21, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 03, 2015	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2020	Published functional studies using HEK293 cells transfected with this variant demonstrate deficient holoenzyme formation (Houge et al., 2015); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32074998, 28554332, 29595814, 26168268, 25533962, 26576547, 25972378, 29288388, 28628100, 28867141, 28135719, 29051493, 29346770, 29296277, 28191890, 31036916, 32156701, 31019026, 31981491, 33338668, 32959227, 33084218, 33098801) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PPP2R5D: PS2:Very Strong, PM1, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 198 of the PPP2R5D protein (p.Glu198Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PPP2R5D-related conditions (PMID: 25533962, 25972378, 26168268). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190286). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PPP2R5D function (PMID: 26168268). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Nov 01, 2019

- -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2017

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PP5_very strong;PM1_moderate;PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Statistical Genetics, Columbia University

Oct 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	4.1	H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.91
MutPred		0.67		Gain of ubiquitination at E198 (P = 0.0048);.;.;.;
MVP		0.85
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.86
gMVP		0.67

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: rs863225082; hg19: chr6-42975003; COSMIC: COSV55150326; COSMIC: COSV55150326;