ClinVar Genomic variation as it relates to human health
NM_006245.4(PPP2R5D):c.1258G>A (p.Glu420Lys)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006245.4(PPP2R5D):c.1258G>A (p.Glu420Lys)
Variation ID: 217912 Accession: VCV000217912.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.1 6: 43009328 (GRCh38) [ NCBI UCSC ] 6: 42977066 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Nov 21, 2015 May 1, 2024 Dec 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006245.4:c.1258G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006236.1:p.Glu420Lys missense NM_001270476.2:c.805G>A NP_001257405.1:p.Glu269Lys missense NM_180976.3:c.1162G>A NP_851307.1:p.Glu388Lys missense NM_180977.3:c.940G>A NP_851308.1:p.Glu314Lys missense NC_000006.12:g.43009328G>A NC_000006.11:g.42977066G>A NG_050636.1:g.29830G>A - Protein change
- E420K, E388K, E269K, E314K
- Other names
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- Canonical SPDI
- NC_000006.12:43009327:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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PPP2R5D | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
462 | 517 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 14, 2023 | RCV000202211.19 | |
Pathogenic (2) |
no assertion criteria provided
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Apr 21, 2017 | RCV001250807.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 30, 2021 | RCV000624654.12 |
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
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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
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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
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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. |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446698.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Macrocephaly (present) , Retrognathia (present) , Hypertelorism (present) , Strabismus (present) , Postaxial hand polydactyly (present) , Hypotonia (present) , Global developmental delay (present)
Sex: male
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Pathogenic
(May 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000256079.4
First in ClinVar: Nov 21, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect; cells expressing the variant constitutively activated AKT-mTOR signaling leading to increased cell size and uncoordinated cell growth compared … (more)
Published functional studies demonstrate a damaging effect; cells expressing the variant constitutively activated AKT-mTOR signaling leading to increased cell size and uncoordinated cell growth compared to WT cells (Papke et al., 2021).; Not observed at significant frequency in large population cohorts (gnomAD); 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: 27479843, 33482199, 29051493, 28867141, 32074998, 26576547, 27535533, 34448180) (less)
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Pathogenic
(Dec 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002236008.3
First in ClinVar: Mar 28, 2022 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 420 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 420 of the PPP2R5D protein (p.Glu420Lys). 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: 26576547). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217912). 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. (less)
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Pathogenic
(Nov 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742270.5
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.1258G>A (p.E420K) alteration is located in coding exon 12 of the PPP2R5D gene. This alteration results from a G to A substitution at nucleotide … (more)
The c.1258G>A (p.E420K) alteration is located in coding exon 12 of the PPP2R5D gene. This alteration results from a G to A substitution at nucleotide position 1258, causing the glutamic acid (E) at amino acid position 420 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 de novo in multiple patients with neurodevelopmental disorders (Shang, 2016; Kurtz-Nelson, 2020). Three patients reported by Shang et al. (2016) had global developmental delay, severe intellectual disability, macrocephaly, hypotonia, autism spectrum disorder, and brain abnormalities. 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). Functional studies using HEK-293 cells with the E420K mutant allele showed changes in kinase/phosphate signaling. Orthogonal validation studies also showed that the E420K-variant cells lead to constitutively active AKT-mTOR signaling, increased cell size, and uncoordinated cellular growth (Papke, 2021). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Apr 21, 2017)
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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
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GenomeConnect - Simons Searchlight
Accession: SCV001443628.1
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 2017-04-21 and interpreted as Pathogenic. Variant was initially … (more)
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-04-21 and interpreted as Pathogenic. Variant was initially reported on 2017-10-03 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. (less)
Clinical Features:
Caesarian section (present) , Poor suck (present) , Strabismus (present) , Generalized hypotonia (present) , Macrocephalus (present) , Gastroesophageal reflux (present) , Otitis media (present) … (more)
Caesarian section (present) , Poor suck (present) , Strabismus (present) , Generalized hypotonia (present) , Macrocephalus (present) , Gastroesophageal reflux (present) , Otitis media (present) , Pneumonia (present) , Abnormality of the respiratory system (present) , Bronchitis (present) , Failure to thrive (present) , Abnormality of the skin (present) , Eczema (present) , Allergy (present) , Lactose intolerance (present) (less)
Age: 0-9 years
Sex: male
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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: SCV001426289.2
First in ClinVar: Aug 03, 2020 Last updated: Oct 01, 2022 |
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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 |
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A disorder-related variant (E420K) of a PP2A-regulatory subunit (PPP2R5D) causes constitutively active AKT-mTOR signaling and uncoordinated cell growth. | Papke CM | The Journal of biological chemistry | 2021 | PMID: 33482199 |
Co-occurring medical conditions among individuals with ASD-associated disruptive mutations. | Kurtz-Nelson EC | Children's health care : journal of the Association for the Care of Children's Health | 2020 | PMID: 33727758 |
PPP2R5D-Related Neurodevelopmental Disorder. | Adam MP | - | 2019 | PMID: 30676711 |
De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism. | Shang L | Neurogenetics | 2016 | PMID: 26576547 |
Text-mined citations for rs863225080 ...
HelpRecord last updated Aug 25, 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.