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.
ClinVar Genomic variation as it relates to human health
NM_006245.4(PPP2R5D):c.592G>A (p.Glu198Lys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(31)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
31
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006245.4(PPP2R5D):c.592G>A (p.Glu198Lys)
Variation ID: 190286 Accession: VCV000190286.64
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6p21.1 6: 43007265 (GRCh38) [ NCBI UCSC ] 6: 42975003 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 19, 2015 Oct 20, 2024 Jan 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006245.4:c.592G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006236.1:p.Glu198Lys missense NM_001270476.2:c.139G>A NP_001257405.1:p.Glu47Lys missense NM_180976.3:c.496G>A NP_851307.1:p.Glu166Lys missense NM_180977.3:c.274G>A NP_851308.1:p.Glu92Lys missense NC_000006.12:g.43007265G>A NC_000006.11:g.42975003G>A NG_050636.1:g.27767G>A Q14738:p.Glu198Lys - Protein change
- E198K, E166K, E92K, E47K
- Other names
- -
- Canonical SPDI
- NC_000006.12:43007264:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PPP2R5D | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
476 | 531 | |
| MEA1 | - | - |
GRCh38 GRCh37 |
15 | 59 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (19) |
criteria provided, multiple submitters, no conflicts
|
Oct 4, 2023 | RCV000170482.40 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2024 | RCV000202079.39 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 24, 2017 | RCV000623917.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 16, 2020 | RCV001261364.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 1, 2019 | RCV001255395.11 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 26, 2021 | RCV001420208.10 |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV002273972.9 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 21, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV000890084.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
|
|
|
Pathogenic
(Oct 30, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Mental retardation, autosomal dominant 35
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000920080.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Nov 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Global developmental delay
Affected status: yes
Allele origin:
de novo
|
Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001431795.1
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
|
|
|
Pathogenic
(Apr 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004040819.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
|
|
Pathogenic
(Oct 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004244501.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
PS2, PS3, PS4, PM1, PM2, PP2, PP3
|
|
|
Pathogenic
(Feb 11, 2016)
|
criteria provided, single submitter
Method: research
|
Hogue-Janssens syndrome 1
Affected status: yes
Allele origin:
de novo
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000265598.2 First in ClinVar: Mar 11, 2016 Last updated: May 29, 2016 |
Clinical Features:
Macrocephaly (present) , Hypotonia (present) , Intellectual disability, moderate (present) , Speech delay (present) , Autism spectrum disorder (present)
|
|
|
Pathogenic
(Jan 01, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
Affected status: yes
Allele origin:
de novo
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000965755.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
|
|
|
Pathogenic
(May 28, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
MENTAL RETARDATION, AUTOSOMAL DOMINANT 35
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996151.1
First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680348.2
First in ClinVar: Feb 08, 2018 Last updated: Feb 03, 2020 |
Observation 1:
Sex: female
Tissue: blood
Observation 2:
Sex: male
Tissue: blood
Observation 3:
Sex: male
Tissue: blood
|
|
|
Pathogenic
(Oct 16, 2020)
|
criteria provided, single submitter
Method: research
|
Intellectual disability
Affected status: yes
Allele origin:
unknown
|
Center for Statistical Genetics, Columbia University
Accession: SCV001438276.1
First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020 |
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448076.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Macrocephaly (present) , Global developmental delay (present) , Generalized hypotonia (present) , Growth delay (present) , Feeding difficulties (present)
Sex: male
|
|
|
Pathogenic
(Apr 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli
Accession: SCV001622628.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
PP5_very strong;PM1_moderate;PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting
Clinical Features:
Global developmental delay (present) , Seizure (present) , Macrocephaly (present) , Hypotonia (present) , Ventriculomegaly (present) , Widened subarachnoid space (present) , Delayed speech and … (more)
Global developmental delay (present) , Seizure (present) , Macrocephaly (present) , Hypotonia (present) , Ventriculomegaly (present) , Widened subarachnoid space (present) , Delayed speech and language development (present) , Abnormal facial shape (present) , Autistic behavior (present) (less)
Sex: male
|
|
|
Pathogenic
(Oct 06, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000256081.1
First in ClinVar: Nov 21, 2015 Last updated: Nov 21, 2015 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002011948.1
First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Bulbous nose (present) , Abnormal facial shape (present) , Hemimegalencephaly (present) , Frontal bossing (present) , Intellectual disability (present) , Protruding ear (present) , Delayed … (more)
Bulbous nose (present) , Abnormal facial shape (present) , Hemimegalencephaly (present) , Frontal bossing (present) , Intellectual disability (present) , Protruding ear (present) , Delayed speech and language development (present) , Abnormal facial shape (present) , Delayed gross motor development (present) , Macrocephaly (present) , Intellectual disability (present) , Delayed fine motor development (present) , Cortical dysplasia (present) (less)
|
|
|
Pathogenic
(Jun 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
Affected status: yes
Allele origin:
de novo
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002506802.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Intellectual disability (present) , Autistic behavior (present) , Absent speech (present) , Macrocephaly (present) , Frontal bossing (present) , Strabismus (present) , Thick vermilion border … (more)
Intellectual disability (present) , Autistic behavior (present) , Absent speech (present) , Macrocephaly (present) , Frontal bossing (present) , Strabismus (present) , Thick vermilion border (present) , Obesity (present) (less)
Secondary finding: no
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental delay
Affected status: yes
Allele origin:
unknown
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559022.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Accession: SCV002568834.1
First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022 |
|
|
|
Pathogenic
(May 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000740978.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Severe global developmental delay (present) , Muscular hypotonia (present) , Macrocephalus (present) , Frontal bossing (present) , Short stature (present) , Seizures (present) , Absent … (more)
Severe global developmental delay (present) , Muscular hypotonia (present) , Macrocephalus (present) , Frontal bossing (present) , Short stature (present) , Seizures (present) , Absent speech (present) , Amblyopia (present) , Myopia (disease) (present) , Astigmatism (present) , Abnormality of the optic nerve (present) , Increased thyroid-stimulating hormone level (present) , Abnormality of long-chain fatty-acid metabolism (present) , Widened subarachnoid space (present) (less)
Sex: male
Ethnicity/Population group: Asian/Cambodian
Observation 2:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian
Observation 3:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Hispanic
Observation 4:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Caucasian
Observation 5:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Hispanic
|
|
|
Pathogenic
(Feb 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002072531.2
First in ClinVar: Feb 05, 2022 Last updated: May 06, 2023 |
Comment:
_x000D_ Criteria applied: PS2, PS3, PS4_MOD, PM1, PM2_SUP, PP3
|
|
|
Pathogenic
(May 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Department of Human Genetics, Hannover Medical School
Accession: SCV003925678.1
First in ClinVar: May 27, 2023 Last updated: May 27, 2023 |
Clinical Features:
Wide anterior fontanel (present) , Seizure (present) , Hypoxemia (present) , Movement disorder (present)
|
|
|
Pathogenic
(Dec 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001583441.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Dec 25, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
Affected status: yes
Allele origin:
de novo
|
Center for Molecular Medicine, Children’s Hospital of Fudan University
Accession: SCV005046466.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
|
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557795.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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 (less)
|
|
|
Pathogenic
(Jan 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246209.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
PPP2R5D: PS2:Very Strong, PM1, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting
Number of individuals with the variant: 7
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001932323.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(Aug 03, 2015)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 35
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000222909.3
First in ClinVar: May 19, 2015 Last updated: Jun 09, 2024 |
Comment on evidence:
In 3 unrelated patients with autosomal dominant intellectual developmental disorder-35 (MRD35; 616355), the Deciphering Developmental Disorders Study (2015) identified a heterozygous de novo missense mutation … (more)
In 3 unrelated patients with autosomal dominant intellectual developmental disorder-35 (MRD35; 616355), the Deciphering Developmental Disorders Study (2015) identified a heterozygous de novo missense mutation in the PPP2R5D gene, a G-to-A transition at chromosome coordinate g.42,975,003 (chr6.42,975,003G-A, GRCh37) resulting in a glu198-to-lys (E198K) substitution. No functional studies were performed. Houge et al. (2015) identified a de novo heterozygous E198K mutation, resulting from a c.592G-A transition (c.592G-A, NM_006245.2), in 3 unrelated patients with MRD35. The mutation occurred in a highly conserved acidic loop that faces the A and C subunits of the PP2A complex. Overexpression of E198K in HEK293 cells resulted in increased phosphorylation of a PPP2R5D substrate, consistent with a dominant-negative effect. The patients with the E198K mutation had a more severe phenotype compared to patients with other PPP2R5D mutations, reflecting the greater impact of the mutation on binding to subunit A and C of the PP2A holocomplex demonstrated in in vitro cellular studies. Loveday et al. (2015) identified a de novo heterozygous E198K mutation (c.592G-A, NM_006245) in a patient (COG1744) with MRD35 associated with overgrowth, including increased head circumference. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present among 1,000 population controls or in the ExAC browser. Functional studies of the variant were not performed, but the mutation occurred in the substrate specificity loop, and Loveday et al. (2015) postulated that it could plausibly alter the ability of PP2A to dephosphorylate target substrates. (less)
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Pathogenic
(Mar 25, 2019)
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no assertion criteria provided
Method: provider interpretation
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Hogue-Janssens syndrome 1
Affected status: yes
Allele origin:
de novo,
unknown
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GenomeConnect - Simons Searchlight
Accession: SCV001443620.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
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 … (more)
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. (less)
Observation 1:
Number of individuals with the variant: 1
Sex: female
Testing laboratory: Genome Diagnostics Laboratory, University Medical Center Utrecht
Date variant was reported to submitter: 2015-02-17
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Induced vaginal delivery (present) , Meconium stained amniotic fluid (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Neonatal hypotonia (present) , Generalized hypotonia … (more)
Induced vaginal delivery (present) , Meconium stained amniotic fluid (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Neonatal hypotonia (present) , Generalized hypotonia (present) , Macrocephalus (present) , Seizures (present) , Otitis media (present) , Myoclonic seizure (present) , Abnormality of temperature regulation (present) , Sleep disturbance (present) (less)
Age: 0-9 years
Sex: male
Testing laboratory: Ambry Genetics
Date variant was reported to submitter: 2018-03-08
Testing laboratory interpretation: Pathogenic
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Induced vaginal delivery (present) , Neonatal seizure (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Abnormality of … (more)
Autistic behavior (present) , Induced vaginal delivery (present) , Neonatal seizure (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Abnormality of vision (present) , Myopia (disease) (present) , Generalized hypotonia (present) , Macrocephalus (present) , Seizures (present) , Focal seizures with impairment of consciousness or awareness (present) , Short stature (present) , Allergy (present) , Lactose intolerance (present) (less)
Age: 20-29 years
Sex: female
Testing laboratory: Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia
Date variant was reported to submitter: 2018-01-29
Testing laboratory interpretation: Likely pathogenic
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Abnormality of vision (present) , Astigmatism (present) , Strabismus (present) , … (more)
Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Abnormality of vision (present) , Astigmatism (present) , Strabismus (present) , Generalized hypotonia (present) , Macrocephalus (present) , Gastroesophageal reflux (present) , Diarrhea (present) , Failure to thrive (present) , Abnormality of the skin (present) , Eczema (present) (less)
Age: 0-9 years
Sex: male
Testing laboratory: University Hospital Tubingen
Date variant was reported to submitter: 2020-08-16
Testing laboratory interpretation: Pathogenic
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
Caesarian section (present) , Neonatal respiratory distress (present) , Neonatal seizure (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy … (more)
Caesarian section (present) , Neonatal respiratory distress (present) , Neonatal seizure (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Strabismus (present) , Generalized hypotonia (present) , Macrocephalus (present) , Seizures (present) , Absence seizures (present) , Gastroesophageal reflux (present) , Diarrhea (present) , Constipation (present) , Abnormality of the skin (present) , Eczema (present) , Allergy (present) , Lactose intolerance (present) , Food allergy (present) (less)
Age: 0-9 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2018-05-29
Testing laboratory interpretation: Pathogenic
Observation 6:
Number of individuals with the variant: 1
Sex: male
Testing laboratory: Genetics - Viapath,Viapath, Guy's Hospital
Date variant was reported to submitter: 2018-07-25
Testing laboratory interpretation: Pathogenic
Observation 7:
Number of individuals with the variant: 1
Sex: female
Testing laboratory: Not Provided
Date variant was reported to submitter: 2018-03-26
Testing laboratory interpretation: Pathogenic
Observation 8:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Caesarian section (present) , Meconium stained amniotic fluid (present) , Neonatal seizure (present) , Hyperbilirubinemia (present) , Poor suck (present) , … (more)
Autistic behavior (present) , Caesarian section (present) , Meconium stained amniotic fluid (present) , Neonatal seizure (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Abnormality of vision (present) , Astigmatism (present) , Strabismus (present) , Optic atrophy (present) , Generalized hypotonia (present) , Macrocephalus (present) , Seizures (present) , Epileptic spasms (present) , Otitis media (present) , Pneumonia (present) , Abnormality of the vasculature (present) , Abnormality of temperature regulation (present) , Sleep disturbance (present) , Abnormality of pain sensation (present) (less)
Age: 0-9 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2018-04-13
Testing laboratory interpretation: Pathogenic
Observation 9:
Number of individuals with the variant: 1
Clinical Features:
Neonatal seizure (present) , Hyperbilirubinemia (present) , Generalized hypotonia (present) , Macrocephalus (present) , Seizures (present) , Gastroesophageal reflux (present) , Constipation (present) , Otitis … (more)
Neonatal seizure (present) , Hyperbilirubinemia (present) , Generalized hypotonia (present) , Macrocephalus (present) , Seizures (present) , Gastroesophageal reflux (present) , Constipation (present) , Otitis media (present) , Abnormality of the skeletal system (present) , Abnormality of the fontanelles or cranial sutures (present) , Abnormality of the skin (present) , Inflammatory abnormality of the skin (present) , Allergy (present) , Food allergy (present) , Abnormality of the cardiovascular system (present) , Myoclonic seizure (present) (less)
Age: 0-9 years
Sex: male
Testing laboratory: Hospital Universitario 12 de Octubre
Date variant was reported to submitter: 2018-12-27
Testing laboratory interpretation: Pathogenic
Observation 10:
Number of individuals with the variant: 1
Sex: male
Testing laboratory: Fulgent Genetics,Fulgent Genetics
Date variant was reported to submitter: 2019-01-02
Testing laboratory interpretation: Pathogenic
Observation 11:
Number of individuals with the variant: 1
Sex: female
Testing laboratory: Ambry Genetics
Date variant was reported to submitter: 2017-06-23
Testing laboratory interpretation: Pathogenic
Observation 12:
Number of individuals with the variant: 1
Sex: female
Testing laboratory: GENDA
Date variant was reported to submitter: 2019-01-24
Testing laboratory interpretation: Pathogenic
Observation 13:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Generalized hypotonia (present) … (more)
Autistic behavior (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Generalized hypotonia (present) , Macrocephalus (present) , Otitis media (present) , Hypospadias, penile (present) , Seizures (present) , Myoclonic seizure (present) (less)
Age: 0-9 years
Sex: male
Testing laboratory: The Institute of Cancer Research
Date variant was reported to submitter: 2017-03-01
Testing laboratory interpretation: Pathogenic
Observation 14:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Caesarian section (present) , Abnormality of vision (present) , Strabismus (present) , Cortical visual impairment (present) , Generalized hypotonia (present) , … (more)
Autistic behavior (present) , Caesarian section (present) , Abnormality of vision (present) , Strabismus (present) , Cortical visual impairment (present) , Generalized hypotonia (present) , Macrocephalus (present) , Seizures (present) , Generalized tonic-clonic seizures (present) , Gastroesophageal reflux (present) , Diarrhea (present) (less)
Age: 10-19 years
Sex: male
Testing laboratory: West Midlands Regional Genetics Laboratories
Date variant was reported to submitter: 2015-01-12
Testing laboratory interpretation: Pathogenic
Observation 15:
Number of individuals with the variant: 1
Clinical Features:
Meconium stained amniotic fluid (present) , Neonatal respiratory distress (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , … (more)
Meconium stained amniotic fluid (present) , Neonatal respiratory distress (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Abnormality of vision (present) , Myopia (disease) (present) , Generalized hypotonia (present) , Macrocephalus (present) , Gastroesophageal reflux (present) , Otitis media (present) , Abnormal heart morphology (present) , Atrial septal defect (present) , Allergy (present) , Lactose intolerance (present) , Drug allergy (present) , Food allergy (present) , Abnormality of the cardiovascular system (present) (less)
Age: 0-9 years
Sex: female
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2015-09-02
Testing laboratory interpretation: Pathogenic
Observation 16:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Caesarian section (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal hypotonia (present) , Hearing … (more)
Autistic behavior (present) , Caesarian section (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal hypotonia (present) , Hearing abnormality (present) , Conductive hearing impairment (present) , Abnormality of vision (present) , Nystagmus (present) , Clumsiness (present) , Generalized hypotonia (present) , Hypertonia (present) , Macrocephalus (present) , Otitis media (present) , Abnormality of the skin (present) , Eczema (present) (less)
Age: 10-19 years
Sex: female
Testing laboratory: Oxford University Genetics Laboratories, Churchill Hospital
Date variant was reported to submitter: 2015-03-26
Testing laboratory interpretation: Pathogenic
Observation 17:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Meconium stained amniotic fluid (present) , Neonatal seizure (present) , Neonatal hypotonia (present) , Abnormality of vision (present) , Astigmatism (present) … (more)
Autistic behavior (present) , Meconium stained amniotic fluid (present) , Neonatal seizure (present) , Neonatal hypotonia (present) , Abnormality of vision (present) , Astigmatism (present) , Generalized hypotonia (present) , Macrocephalus (present) , Cerebral palsy (present) , Seizure precipitated by febrile infection (present) , Seizures (present) , Generalized tonic-clonic seizures (present) , Otitis media (present) , Abnormality of the respiratory system (present) , Bronchitis (present) , Menstrual irregularities (present) , Abnormality of the skeletal system (present) , Scoliosis (present) , Abnormality of the skin (present) , Eczema (present) , Allergy (present) , Drug allergy (present) , Food allergy (present) (less)
Age: 20-29 years
Sex: female
Testing laboratory: Belfast City Hospital
Date variant was reported to submitter: 2012-10-01
Testing laboratory interpretation: Pathogenic
Observation 18:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Oligohydramnios (present) , Caesarian section (present) , Meconium stained amniotic fluid (present) , Neonatal respiratory distress (present) , Neonatal hypotonia (present) … (more)
Autistic behavior (present) , Oligohydramnios (present) , Caesarian section (present) , Meconium stained amniotic fluid (present) , Neonatal respiratory distress (present) , Neonatal hypotonia (present) , Abnormality of vision (present) , Myopia (disease) (present) , Astigmatism (present) , Strabismus (present) , Clumsiness (present) , Generalized hypotonia (present) , Hypertonia (present) , Macrocephalus (present) , Bulbar palsy (present) , Cerebral palsy (present) , Gastroesophageal reflux (present) , Diarrhea (present) , Otitis media (present) , Pneumonia (present) , Abnormality of the respiratory system (present) , Pneumonia (present) , Abnormality of the urinary system (present) , Stage 5 chronic kidney disease (present) , Failure to thrive (present) , Short stature (present) , Growth hormone deficiency (present) , Allergy (present) , Lactose intolerance (present) , Food allergy (present) (less)
Age: 10-19 years
Sex: male
Testing laboratory: North East Thames Regional Genetics Service
Date variant was reported to submitter: 2017-09-18
Testing laboratory interpretation: Pathogenic
Observation 19:
Number of individuals with the variant: 1
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2015-12-20
Testing laboratory interpretation: Pathogenic
Observation 20:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Premature birth (present) , Caesarian section (present) , Nuchal cord (present) , Poor suck (present) , Feeding difficulties in infancy (present) … (more)
Autistic behavior (present) , Premature birth (present) , Caesarian section (present) , Nuchal cord (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Abnormality of vision (present) , Nystagmus (present) , Astigmatism (present) , Strabismus (present) , Generalized hypotonia (present) , Macrocephalus (present) , Seizures (present) , Focal seizures without impairment of consciousness or awareness (present) , Gastroesophageal reflux (present) (less)
Age: 0-9 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-03-23
Testing laboratory interpretation: Pathogenic
Observation 21:
Number of individuals with the variant: 1
Clinical Features:
Meconium stained amniotic fluid (present) , Neonatal respiratory distress (present) , Neonatal hypotonia (present) , Nystagmus (present) , Generalized hypotonia (present) , Macrocephalus (present) , … (more)
Meconium stained amniotic fluid (present) , Neonatal respiratory distress (present) , Neonatal hypotonia (present) , Nystagmus (present) , Generalized hypotonia (present) , Macrocephalus (present) , Otitis media (present) (less)
Age: 0-9 years
Sex: female
Testing laboratory: Centogene AG - the Rare Disease Company
Date variant was reported to submitter: 2016-05-31
Testing laboratory interpretation: Pathogenic
Observation 22:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) … (more)
Autistic behavior (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Nystagmus (present) , Strabismus (present) , Generalized hypotonia (present) , Macrocephalus (present) , Gastroesophageal reflux (present) , Failure to thrive (present) , Short stature (present) , Abnormality of the skin (present) , Eczema (present) , Allergy (present) , Food allergy (present) (less)
Age: 10-19 years
Sex: male
Testing laboratory: MNG Laboratories (Medical Neurogenetics, LLC.)
Date variant was reported to submitter: 2016-06-20
Testing laboratory interpretation: Pathogenic
Observation 23:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Caesarian section (present) , Breech presentation (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal … (more)
Autistic behavior (present) , Caesarian section (present) , Breech presentation (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Abnormality of vision (present) , Myopia (disease) (present) , Generalized hypotonia (present) , Macrocephalus (present) , Seizures (present) , Focal seizures without impairment of consciousness or awareness (present) , Abnormality of the respiratory system (present) , Asthma (present) , Abnormality of the skin (present) , Eczema (present) (less)
Age: 10-19 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-12-12
Testing laboratory interpretation: not provided
Observation 24:
Number of individuals with the variant: 1
Clinical Features:
Ventouse delivery (present) , Poor suck (present) , Neonatal hypotonia (present) , Abnormality of vision (present) , Myopia (disease) (present) , Clumsiness (present) , Generalized … (more)
Ventouse delivery (present) , Poor suck (present) , Neonatal hypotonia (present) , Abnormality of vision (present) , Myopia (disease) (present) , Clumsiness (present) , Generalized hypotonia (present) , Macrocephalus (present) , Abnormality of the skeletal system (present) , Scoliosis (present) (less)
Age: 10-19 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2014-04-09
Testing laboratory interpretation: Pathogenic
Observation 25:
Number of individuals with the variant: 1
Clinical Features:
Caesarian section (present) , Poor suck (present) , Neonatal hypotonia (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Otitis media (present) , Abnormality … (more)
Caesarian section (present) , Poor suck (present) , Neonatal hypotonia (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Otitis media (present) , Abnormality of the respiratory system (present) , Bronchitis (present) , Short stature (present) , Obesity (present) , Allergy (present) , Food allergy (present) (less)
Age: 0-9 years
Sex: male
Testing laboratory: DNA Alliance
Date variant was reported to submitter: 2016-03-15
Testing laboratory interpretation: Pathogenic
Observation 26:
Number of individuals with the variant: 1
Clinical Features:
Hyperbilirubinemia (present) , Neonatal hypotonia (present) , Strabismus (present) , Generalized hypotonia (present) , Hypertonia (present) , Otitis media (present) , Abnormality of the urinary … (more)
Hyperbilirubinemia (present) , Neonatal hypotonia (present) , Strabismus (present) , Generalized hypotonia (present) , Hypertonia (present) , Otitis media (present) , Abnormality of the urinary system (present) , Renal agenesis (present) (less)
Age: 0-9 years
Sex: female
Testing laboratory: Hadassah The Women's Zionist Organization of America
Date variant was reported to submitter: 2016-07-17
Testing laboratory interpretation: not provided
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Pathogenic
(May 13, 2021)
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no assertion criteria provided
Method: clinical testing
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Hogue-Janssens syndrome 1
Affected status: yes
Allele origin:
de novo
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Pediatric Genetics Clinic, Sheba Medical Center
Accession: SCV001712211.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Clinical Features:
Global developmental delay (present) , Macrocephaly (present) , Abnormal facial shape (present) , Abnormal cerebellar vermis morphology (present) , Autism (present)
Secondary finding: no
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Hogue-Janssens syndrome 1
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760182.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959857.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Hogue-Janssens syndrome 1
Affected status: unknown
Allele origin:
de novo
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GeneReviews
Accession: SCV001426292.2
First in ClinVar: Aug 03, 2020 Last updated: Oct 01, 2022 |
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Comment:
Comment:
PS2, PS3, PS4, PM1, PM2, PP2, PP3
Comment:
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.
Comment:
PP5_very strong;PM1_moderate;PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
_x000D_ Criteria applied: PS2, PS3, PS4_MOD, PM1, PM2_SUP, PP3
Comment:
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.
Comment:
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
Comment:
PPP2R5D: PS2:Very Strong, PM1, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
PS2, PS3, PS4, PM1, PM2, PP2, PP3
Comment:
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.
Comment:
PP5_very strong;PM1_moderate;PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
_x000D_ Criteria applied: PS2, PS3, PS4_MOD, PM1, PM2_SUP, PP3
Comment:
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.
Comment:
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
Comment:
PPP2R5D: PS2:Very Strong, PM1, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder. | Biswas D | International journal of molecular sciences | 2020 | PMID: 32074998 |
| PPP2R5D-Related Neurodevelopmental Disorder. | Adam MP | - | 2019 | PMID: 30676711 |
| Corrigendum: Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth. | Loveday C | Human molecular genetics | 2019 | PMID: 30615140 |
| Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism. | Yeung KS | Molecular autism | 2017 | PMID: 29296277 |
| Genomic diagnosis for children with intellectual disability and/or developmental delay. | Bowling KM | Genome medicine | 2017 | PMID: 28554332 |
| Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. | Kosmicki JA | Nature genetics | 2017 | PMID: 28191890 |
| B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. | Houge G | The Journal of clinical investigation | 2015 | PMID: 26168268 |
| Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth. | Loveday C | Human molecular genetics | 2015 | PMID: 25972378 |
| Large-scale discovery of novel genetic causes of developmental disorders. | Deciphering Developmental Disorders Study | Nature | 2015 | PMID: 25533962 |
Text-mined citations for this variant ...
HelpRecord last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.