rs863225082

Variant names:

• chr6-43007265-G-A
• rs863225082
• NM_006245.4:c.592G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-43007265-G-A
• chr6-43007265-G-T

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 the same amino acid substitution has been previously reported as Likely pathogenic in 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 the PPP2R5D gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 3.6476 (above the threshold of 3.09). Trascript score misZ: 4.9069 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
PPP2R5D	NM_006245.4	c.592G>A	p.Glu198Lys	missense_variant	Exon 5 of 16	ENST00000485511.6	NP_006236.1
PPP2R5D	NM_180976.3	c.496G>A	p.Glu166Lys	missense_variant	Exon 5 of 16		NP_851307.1
PPP2R5D	NM_180977.3	c.274G>A	p.Glu92Lys	missense_variant	Exon 3 of 14		NP_851308.1
PPP2R5D	NM_001270476.2	c.139G>A	p.Glu47Lys	missense_variant	Exon 5 of 16		NP_001257405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R5D	ENST00000485511.6	c.592G>A	p.Glu198Lys	missense_variant	Exon 5 of 16	1	NM_006245.4	ENSP00000417963.1
PPP2R5D	ENST00000394110.7	c.496G>A	p.Glu166Lys	missense_variant	Exon 5 of 16	1		ENSP00000377669.3

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

Dec 25, 2020

Center for Molecular Medicine, Children’s Hospital of Fudan University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2023

Department of Human Genetics, Hannover Medical School

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2019

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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. -

May 28, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 30, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 11, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 13, 2021

Pediatric Genetics Clinic, Sheba Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2015

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2018

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 31618753). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000242521 /PMID: 18626973 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jun 11, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 07, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PS2, PS3, PS4_MOD, PM1, PM2_SUP, PP3 -

Aug 03, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 04, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS3, PS4, PM1, PM2, PP2, PP3 -

Jun 21, 2018

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:7

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 06, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

-

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PPP2R5D: PS2:Very Strong, PM1, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting -

Global developmental delay Pathogenic:1

Nov 01, 2019

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodevelopmental delay Pathogenic:1

-

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

May 24, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Pathogenic:1

Apr 26, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Intellectual disability Pathogenic:1

Oct 16, 2020

Center for Statistical Genetics, Columbia University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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;.;.;.
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;