ClinVar Genomic variation as it relates to human health
NM_006245.4(PPP2R5D):c.758G>A (p.Arg253Gln)
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.
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(1); Likely pathogenic(1); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006245.4(PPP2R5D):c.758G>A (p.Arg253Gln)
Variation ID: 429222 Accession: VCV000429222.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6p21.1 6: 43007966 (GRCh38) [ NCBI UCSC ] 6: 42975704 (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 Jul 2, 2017 Apr 15, 2024 Apr 4, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_006245.4:c.758G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006236.1:p.Arg253Gln missense NM_001270476.2:c.305G>A NP_001257405.1:p.Arg102Gln missense NM_180976.3:c.662G>A NP_851307.1:p.Arg221Gln missense NM_180977.3:c.440G>A NP_851308.1:p.Arg147Gln missense NC_000006.12:g.43007966G>A NC_000006.11:g.42975704G>A NG_050636.1:g.28468G>A - Protein change
- R253Q, R221Q, R102Q, R147Q
- Other names
- -
- Canonical SPDI
- NC_000006.12:43007965: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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
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 |
456 | 510 |
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Apr 4, 2024 | RCV000626280.16 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Oct 9, 2023 | RCV001696916.15 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(May 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Mental retardation, autosomal dominant 35
Affected status: unknown
Allele origin:
unknown
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746937.2
First in ClinVar: Apr 29, 2018 Last updated: May 31, 2020 |
|
|
Uncertain significance
(Oct 31, 2017)
|
criteria provided, single submitter
Method: provider interpretation, clinical testing
|
Hogue-Janssens syndrome 1
Affected status: unknown
Allele origin:
paternal
|
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System
Accession: SCV000804328.2
First in ClinVar: Apr 29, 2018 Last updated: Dec 11, 2022 |
Comment:
This 5 year old male has a history of global developmental delay, macrocephaly, hypotonia, vision abnormalities, torticollis, and plagiocephaly. This variant is absent from gnomAD … (more)
This 5 year old male has a history of global developmental delay, macrocephaly, hypotonia, vision abnormalities, torticollis, and plagiocephaly. This variant is absent from gnomAD but present in ExAC at a frequency of 0.0008121% overall. Computational models suggest that this variant is probably damaging to protein structure and/or function. The variant was inherited from the patient's father who has a history of dyslexia and who required learning supports in elementary school. Pathogenic de novo missense variants in PPP2R5D have been reported in individuals with intellectual disability, autism spectrum disorder, macrocephaly, hypotonia, increased height, seizures, and dysmorphic features (PMID:25972378; PMID:26576547). (less)
Observation 1:
Clinical Features:
Macrocephalus (present) , Global developmental delay (present) , Muscular hypotonia (present) , Torticollis (present) , Plagiocephaly (present)
Age: 0-9 years
Sex: male
Secondary finding: no
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-05-07
Testing laboratory interpretation: Uncertain significance
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Macrocephalus (present) , Global developmental delay (present) , Muscular hypotonia (present) , Torticollis (present) , Plagiocephaly (present)
Age: 0-9 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-05-07
Testing laboratory interpretation: Uncertain significance
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV003924072.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
A Heterozygous Missense variant c.758G>A in Exon 7 of the PPP2R5D gene that results in the amino acid substitution p.Arg253Gln was identified. The observed variant … (more)
A Heterozygous Missense variant c.758G>A in Exon 7 of the PPP2R5D gene that results in the amino acid substitution p.Arg253Gln was identified. The observed variant has a minor allele frequency of 0.00001% in gnomAD exomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Likely Pathogenic and Uncertain Significance (variant ID: 429222). This variant has previously been reported for neurodevelopmental disorders (Krgovic D et al., 2022). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
|
|
Pathogenic
(Oct 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000581731.7
First in ClinVar: Jul 02, 2017 Last updated: Nov 25, 2023 |
Comment:
Reported heterozygous in a patient with autism and intellectual disability in published literature without additional clinical information or familial segregation information (Krgovic et al., 2022); … (more)
Reported heterozygous in a patient with autism and intellectual disability in published literature without additional clinical information or familial segregation information (Krgovic et al., 2022); 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: 35813072, 37167322, 36833222) (less)
|
|
Uncertain significance
(Mar 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003328893.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 429222). This variant has not been reported in the literature in individuals affected with PPP2R5D-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 253 of the PPP2R5D protein (p.Arg253Gln). (less)
|
|
Uncertain significance
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hogue-Janssens syndrome 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004810253.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Impaired Neurodevelopmental Genes in Slovenian Autistic Children Elucidate the Comorbidity of Autism With Other Developmental Disorders. | Krgovic D | Frontiers in molecular neuroscience | 2022 | PMID: 35813072 |
De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism. | Shang L | Neurogenetics | 2016 | PMID: 26576547 |
Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth. | Loveday C | Human molecular genetics | 2015 | PMID: 25972378 |
Text-mined citations for rs1131691266 ...
HelpRecord last updated Jun 02, 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.