chr6-43007271-G-A

Variant names:

• chr6-43007271-G-A
• rs863225079
• NM_006245.4:c.598G>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. 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 (★★).

• 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 13 ACMG points.

• 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, 0.881
• 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 rank	MANE	Protein	UniProt
PPP2R5D	NM_006245.4	c.598G>A	p.Glu200Lys	missense_variant	Exon 5 of 16	ENST00000485511.6	NP_006236.1
PPP2R5D	NM_180976.3	c.502G>A	p.Glu168Lys	missense_variant	Exon 5 of 16		NP_851307.1
PPP2R5D	NM_180977.3	c.280G>A	p.Glu94Lys	missense_variant	Exon 3 of 14		NP_851308.1
PPP2R5D	NM_001270476.2	c.145G>A	p.Glu49Lys	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.598G>A	p.Glu200Lys	missense_variant	Exon 5 of 16	1	NM_006245.4	ENSP00000417963.1
PPP2R5D	ENST00000394110.7	c.502G>A	p.Glu168Lys	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/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

Mar 12, 2020

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Dec 05, 2023

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Oct 18, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 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 2019-03-11 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -

Dec 11, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]. -

Nov 10, 2023

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 22, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 26, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 28, 2019

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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] -

Feb 10, 2022

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2023

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.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. -

not provided Pathogenic:9

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 20, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS4, PP3, PM2 -

Dec 06, 2023

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 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. -

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

- -

Nov 03, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Sep 23, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;.;.;.
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;