Submissions for variant NM_006245.4(PPP2R5D):c.598G>A (p.Glu200Lys)

dbSNP: rs863225079

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000202069	SCV000256078	pathogenic	not provided	2021-11-03	criteria provided, single submitter	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)
Eurofins Ntd Llc (ga)	RCV000202069	SCV000855711	pathogenic	not provided	2017-07-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000202069	SCV001246210	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	PPP2R5D: PS2:Very Strong, PM2, PS4:Moderate, PP2, PS3:Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000202069	SCV001411044	pathogenic	not provided	2023-12-06	criteria provided, single submitter	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000201454	SCV001428633	pathogenic	Hogue-Janssens syndrome 1	2017-02-22	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
Ambry Genetics	RCV001265718	SCV001443887	pathogenic	Inborn genetic diseases	2022-09-23	criteria provided, single submitter	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000202069	SCV001447412	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV000201454	SCV001573013	pathogenic	Hogue-Janssens syndrome 1	2020-03-12	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000202069	SCV002051502	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing	PS2, PS4, PP3, PM2
Revvity Omics, Revvity	RCV000201454	SCV003818545	pathogenic	Hogue-Janssens syndrome 1	2022-03-26	criteria provided, single submitter	clinical testing
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000201454	SCV003840192	likely pathogenic	Hogue-Janssens syndrome 1	2022-02-10	criteria provided, single submitter	clinical testing
Daryl Scott Lab, Baylor College of Medicine	RCV000201454	SCV004102727	pathogenic	Hogue-Janssens syndrome 1	2023-11-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000201454	SCV004241146	pathogenic	Hogue-Janssens syndrome 1	2023-12-15	criteria provided, single submitter	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.
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV000201454	SCV005046470	pathogenic	Hogue-Janssens syndrome 1	2023-10-18	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000201454	SCV005088760	pathogenic	Hogue-Janssens syndrome 1	2021-12-11	criteria provided, single submitter	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].
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000201454	SCV005091069	pathogenic	Hogue-Janssens syndrome 1	2023-12-05	criteria provided, single submitter	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).
OMIM	RCV000201454	SCV000256115	pathogenic	Hogue-Janssens syndrome 1	2015-08-03	no assertion criteria provided	literature only
GeneReviews	RCV000201454	SCV001426293	not provided	Hogue-Janssens syndrome 1		no assertion provided	literature only
Clinical Genomics Laboratory, Stanford Medicine	RCV000201454	SCV001427093	pathogenic	Hogue-Janssens syndrome 1	2019-10-28	no assertion criteria provided	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]
GenomeConnect - Simons Searchlight	RCV000201454	SCV001443619	pathogenic	Hogue-Janssens syndrome 1	2019-03-11	no assertion criteria provided	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000202069	SCV001740221	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202069	SCV001959413	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000202069	SCV001973221	pathogenic	not provided		no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV000201454	SCV005091337	likely pathogenic	Hogue-Janssens syndrome 1	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team
PreventionGenetics, part of Exact Sciences	RCV004737321	SCV005354439	pathogenic	PPP2R5D-related disorder	2024-07-18	no assertion criteria provided	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.