chr6-43007271-G-A

Position:

• chr6-43007271-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_006245.4(PPP2R5D):​c.598G>A​(p.Glu200Lys) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E200Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24 O:1
• Conservation: PhyloP100: 9.95

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.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_006245.4
• 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, 0.881
• PP5: Variant 6-43007271-G-A is Pathogenic according to our data. Variant chr6-43007271-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43007271-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP2R5D	NM_006245.4	c.598G>A	p.Glu200Lys	missense_variant	5/16	ENST00000485511.6
PPP2R5D	NM_180976.3	c.502G>A	p.Glu168Lys	missense_variant	5/16
PPP2R5D	NM_180977.3	c.280G>A	p.Glu94Lys	missense_variant	3/14
PPP2R5D	NM_001270476.2	c.145G>A	p.Glu49Lys	missense_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP2R5D	ENST00000485511.6	c.598G>A	p.Glu200Lys	missense_variant	5/16	1	NM_006245.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hogue-Janssens syndrome 1 Pathogenic:13 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 22, 2017	This variant was identified as de novo (maternity and paternity confirmed). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Oct 28, 2019	The p.Glu200Lys variant has been previously reported in at least 6 unrelated individuals with clinical features of PPP2R5D-related neurodevelopmental disorder, and was identified de novo in this individual and in 5 previously reported individuals (Houge et al., 2015; Loveday et al., 2015; Shang et al., 2016; Reijnders et al., 2017). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Glu200Lys variant is located in a conserved acidic loop domain of PPP2R5D where other pathogenic and likely pathogenic variants have been described, and functional studies suggest the p.Glu200Lys variant reduces binding to other protein phosphatase 2A subunits (Houge et al., 2015). Additionally, the PPP2R5D gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Glu200Lys variant as pathogenic for autosomal dominant PPP2R5D-related neurodevelopmental disorder based on the information above. [ACMG evidence codes used: PS2_very strong; PS3_moderate; PM2; PP2] -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Mar 12, 2020	- -
Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Mar 11, 2019	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-03-11 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	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Dec 11, 2021	This variant was previously reported in unrelated individuals with PPP2R5D-related neurodevelopmental disorder and was identified de novo in one individual [PMID: 26168268, 25972378, 29051493, 26576547]. Functional studies suggested that this variant reduces binding to other protein phosphatase 2A subunits [PMID: 26168268]. -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	Feb 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Dec 05, 2023	PS4, PS3, PM2, PP3, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 217456). This variant has been previously reported as causative for PPP2R5D-related neurodevelopmental disorders (PMID:36216457). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2023	Variant summary: PPP2R5D c.598G>A (p.Glu200Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes (gnomAD). c.598G>A has been reported in the literature in multiple individuals affected with Intellectual Disability and this variant has been reported in de novo occurrences (Houge_2015, Loveday_2015, Reijnders_2017, Dong_2020, Oyama_2022). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant affects PPP2R5D protein function (Houge_2015, Oyama_2022). The following publications have been ascertained in the context of this evaluation (PMID: 32005694, 26168268, 25972378, 29051493, 36216457). 15 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=14) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	Oct 18, 2023	- -

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2021	Published functional studies demonstrate a damaging effect: deficient holoenzyme formation with some residual binding capability in vitro (Houge et al., 2015); Not observed in large population cohorts (Lek et al., 2016); 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: 26576547, 25972378, 26168268, 28867141, 29051493, 30676711, 32743835, 33240318) -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 01, 2020	PS2, PS4, PP3, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 200 of the PPP2R5D protein (p.Glu200Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PPP2R5D-related syndromic intellectual disability (PMID: 26168268). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217456). 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. For these reasons, this variant has been classified as Pathogenic. -
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	Eurofins Ntd Llc (ga)	Jul 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PPP2R5D: PS2:Very Strong, PM2, PS4:Moderate, PP2, PS3:Supporting -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2022

The c.598G>A (p.E200K) alteration is located in coding exon 5 of the PPP2R5D gene. This alteration results from a G to A substitution at nucleotide position 598, causing the glutamic acid (E) at amino acid position 200 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as de novo in several unrelated individuals with developmental delay, intellectual disability, and other features such as overgrowth, dysmorphism, parkinsonism, and hypotonia (Loveday, 2015; Dong, 2020; Kim, 2020; Houge, 2015). In addition, this alteration has been detected in the heterozygous state in multiple individuals with various clinical features of PPP2R5D-related neurodevelopmental disorder (van der Ven, 2021; Levchenko, 2022; Kim, 2020; Loveday, 2015). 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. -

PPP2R5D-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2024

The PPP2R5D c.598G>A variant is predicted to result in the amino acid substitution p.Glu200Lys. This is a recurrent de novo variant that has been reported to be causative for autosomal dominant Houge-Janssens syndrome 1 (Houge et al. 2015. PubMed ID: 26168268; Loveday et al. 2015. PubMed ID: 25972378; Tables S6 and S10, Lelieveld et al. 2017. PubMed ID: 28867141; Reijnders et al. 2017. PubMed ID: 29051493). This variant has also been confirmed to have arisen de novo in an individual undergoing neurodevelopmental disorder testing (Internal Data, PreventionGenetics). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	4.1	H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.99	D;D;.;D
Vest4		0.92
MutPred		0.73		Gain of ubiquitination at E200 (P = 0.0121);.;.;.;
MVP		0.83
MPC		2.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.78
gMVP		0.69

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: rs863225079; hg19: chr6-42975009;