ClinVar Genomic variation as it relates to human health
NM_006245.4(PPP2R5D):c.619T>C (p.Trp207Arg)
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.619T>C (p.Trp207Arg)
Variation ID: 280435 Accession: VCV000280435.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.1 6: 43007292 (GRCh38) [ NCBI UCSC ] 6: 42975030 (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 Dec 19, 2017 Feb 20, 2024 Aug 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006245.4:c.619T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006236.1:p.Trp207Arg missense NM_001270476.2:c.166T>C NP_001257405.1:p.Trp56Arg missense NM_180976.3:c.523T>C NP_851307.1:p.Trp175Arg missense NM_180977.3:c.301T>C NP_851308.1:p.Trp101Arg missense NC_000006.12:g.43007292T>C NC_000006.11:g.42975030T>C NG_050636.1:g.27794T>C Q14738:p.Trp207Arg - Protein change
- W207R, W101R, W175R, W56R
- Other names
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- Canonical SPDI
- NC_000006.12:43007291:T:C
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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 |
447 | 501 |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 3, 2023 | RCV000307513.8 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Aug 21, 2023 | RCV001265481.7 |
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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Likely 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: SCV001447627.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hypotonia (present) , Corpus callosum, agenesis of (present) , Developmental regression (present) , Corpus callosum, agenesis of (present) , Hypotonia (present) , Developmental regression (present) … (more)
Hypotonia (present) , Corpus callosum, agenesis of (present) , Developmental regression (present) , Corpus callosum, agenesis of (present) , Hypotonia (present) , Developmental regression (present) , Seizure (present) , Clubfoot (present) , Plagiocephaly (present) (less)
Sex: male
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Pathogenic
(Apr 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hogue-Janssens syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001571363.1
First in ClinVar: Apr 18, 2021 Last updated: Apr 18, 2021 |
Family history: no
Secondary finding: no
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Pathogenic
(Jun 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
de novo
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503343.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Jun 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hogue-Janssens syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557101.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
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. While loss-of-function was demonstrated, the possibility of dominant-negative has not been excluded and is also a proposed mechanism (PMID: 32074998, 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 tryptophan to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Trp207Cys) and p.(Trp207Leu) were each seen in at least one de novo individual with PPP2R5D-related intelectual disability (DECIPHER, PMID:33628804). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in many individuals with PPP2R5D-related intellectual disability (MIM#616355), including at least four de novo reports (ClinVar, DECIPHER, PMID: 24896178, 26168268). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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)
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hogue-Janssens syndrome 1
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573379.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280435). A different missense change at the same codon (p.Trp207Cys) has been reported to be associated with PPP2R5D-related disorder (ClinVar ID: VCV001333678/ 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Intellectual disability, mild (present) , Seizure (present) , EEG abnormality (present) , Happy demeanor (present) , Recurrent hand flapping (present) … (more)
Global developmental delay (present) , Intellectual disability, mild (present) , Seizure (present) , EEG abnormality (present) , Happy demeanor (present) , Recurrent hand flapping (present) , Paroxysmal bursts of laughter (present) (less)
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Pathogenic
(Apr 07, 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: SCV000330348.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Reported in a large cohort of individuals with intellectual disability and/or developmental delays who had de novo variants identified by exome trio analysis; however no … (more)
Reported in a large cohort of individuals with intellectual disability and/or developmental delays who had de novo variants identified by exome trio analysis; however no case specific information was provided (Lelieveld et al., 2017); Same amino acid substitution caused by a different nucleotide change (c.619T>A) has been reported as a de novo variant in the published literature in association with intellectual disability (Gilissen et al., 2014; Houge et al., 2015; HGMD); Not observed 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: 34448180, 33106617, 28867141, 33726816, 31785789, 33628804, 32074998, 34228795) (less)
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Pathogenic
(Mar 03, 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: SCV004293638.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 280435). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp207 … (more)
ClinVar contains an entry for this variant (Variation ID: 280435). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp207 amino acid residue in PPP2R5D. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PPP2R5D function (PMID: 26168268). 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. This missense change has been observed in individual(s) with PPP2R5D-related conditions (PMID: 24896178). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 207 of the PPP2R5D protein (p.Trp207Arg). (less)
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Pathogenic
(Aug 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hogue-Janssens syndrome 1
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004563725.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The PPP2R5D c.619T>C; p.Trp207Arg variant (rs869320691) is reported in the literature as a de novo variant in large neurodevelopmental disorder or intellectual disability cohorts (Chen … (more)
The PPP2R5D c.619T>C; p.Trp207Arg variant (rs869320691) is reported in the literature as a de novo variant in large neurodevelopmental disorder or intellectual disability cohorts (Chen 2021, Lelieveld 2017, Turner 2019). This variant is also reported in ClinVar (Variation ID: 280435). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, another variant resulting in the same amino acid change, c.619T>A; p.Trp207Arg, is reported in several patients affected with Hogue-Janssens syndrome, also as a de novo variant (Gilissen 2014, Houge 2015). Functional analyses of the p.Trp207Arg variant protein demonstrate impaired subunit binding (Houge 2015) and computational analyses predict that this variant is deleterious (REVEL: 0.795). Based on available information, the c.619T>C; p.Trp207Arg variant is considered to be pathogenic. References: Chen Y et al. Comprehensive genome sequencing analyses identify novel gene mutations and copy number variations associated with infant developmental delay or intellectual disability (DD/ID). Genes Dis. 2021 Dec 3;9(5):1166-1169. PMID: 35873028. Gilissen C et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014 Jul 17;511(7509):344-7. PMID: 24896178. Houge G et al. B56delta-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. J Clin Invest. 2015 Aug 3;125(8):3051-62. PMID: 26168268. Lelieveld SH et al. Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes. Am J Hum Genet. 2017 Sep 7;101(3):478-484. PMID: 28867141. Turner TN et al. Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders. Am J Hum Genet. 2019 Dec 5;105(6):1274-1285. PMID: 31785789. (less)
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Pathogenic
(Sep 05, 2018)
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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: SCV001443622.1
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 2018-09-05 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 2018-09-05 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
Clinical Features:
Autistic behavior (present) , Premature birth (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal hypotonia (present) , Abnormality … (more)
Autistic behavior (present) , Premature birth (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal hypotonia (present) , Abnormality of vision (present) , Astigmatism (present) , Generalized hypotonia (present) , Macrocephalus (present) , Seizures (present) , Generalized tonic-clonic seizures (present) , Focal seizures with impairment of consciousness or awareness (present) , Constipation (present) , Pneumonia (present) , Abnormality of the respiratory system (present) , Pneumonia (present) (less)
Age: 0-9 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-09-18
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Caesarian section (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Generalized hypotonia (present) , Macrocephalus (present) , Seizures (present) , Focal … (more)
Caesarian section (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Generalized hypotonia (present) , Macrocephalus (present) , Seizures (present) , Focal seizures with impairment of consciousness or awareness (present) , Gastroesophageal reflux (present) , Constipation (present) , Otitis media (present) , Abnormality of the skin (present) , Hemangioma (present) , Strabismus (present) (less)
Age: 0-9 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2016-04-11
Testing laboratory interpretation: Pathogenic
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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 Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype. | Yan L | BioMed research international | 2021 | PMID: 33628804 |
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 |
Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes. | Lelieveld SH | American journal of human genetics | 2017 | PMID: 28867141 |
B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. | Houge G | The Journal of clinical investigation | 2015 | PMID: 26168268 |
Genome sequencing identifies major causes of severe intellectual disability. | Gilissen C | Nature | 2014 | PMID: 24896178 |
Text-mined citations for rs869320691 ...
HelpRecord last updated Apr 15, 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.