ClinVar Genomic variation as it relates to human health
NM_001429.3(EP300):c.3857A>G
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_001429.3(EP300):c.3857A>G
Variation ID: 378053 Accession: VCV000378053.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.2 22: 41166649 (GRCh38) [ NCBI UCSC ] 22: 41562653 (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 Mar 8, 2017 Feb 14, 2024 Aug 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001429.4:c.3857A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001420.2:p.Asn1286Ser missense NM_001362843.2:c.3779A>G NP_001349772.1:p.Asn1260Ser missense NC_000022.11:g.41166649A>G NC_000022.10:g.41562653A>G NG_009817.1:g.79040A>G LRG_1422:g.79040A>G LRG_1422t1:c.3857A>G LRG_1422p1:p.Asn1286Ser - Protein change
- N1286S, N1260S
- Other names
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- Canonical SPDI
- NC_000022.11:41166648:A:G
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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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EP300 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1519 | 1651 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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May 22, 2022 | RCV000439427.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 10, 2020 | RCV001260706.9 | |
Pathogenic (1) |
criteria provided, single submitter
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May 9, 2022 | RCV002244870.10 | |
See cases
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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 3, 2021 | RCV002252119.9 |
EP300-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Aug 20, 2023 | RCV003401414.4 |
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
(Sep 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability
Affected status: yes
Allele origin:
de novo
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Diagnostic Laboratory, Strasbourg University Hospital
Accession: SCV001437798.1
First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020 |
Method: targeted next-gen sequencing
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Pathogenic
(Jan 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Rubinstein-Taybi syndrome due to EP300 haploinsufficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001581591.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Rubinstein–Taybi syndrome (PMID: 27648933, 27465822). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 378053). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 1286 of the EP300 protein (p.Asn1286Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. (less)
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Likely pathogenic
(Aug 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Rubinstein-Taybi syndrome due to EP300 haploinsufficiency
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV002028307.1
First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021 |
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Rubinstein-Taybi syndrome due to EP300 haploinsufficiency
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521376.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: 0.39). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000378053). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 27465822, 32827181, 33644862). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 27648933). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Severe short stature (present) , Global developmental delay (present) , Intellectual disability (present) , Pointed chin (present) , Mild microcephaly (present) , Failure to thrive … (more)
Severe short stature (present) , Global developmental delay (present) , Intellectual disability (present) , Pointed chin (present) , Mild microcephaly (present) , Failure to thrive (present) , Epicanthus (present) , Pallor (present) , Anxiety (present) , Strabismus (present) (less)
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Likely pathogenic
(Sep 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523993.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PS4, PM2, PM6
Clinical Features:
Prominent fingertip pads (present) , Neurodevelopmental abnormality (present) , Microcephaly (present) , Epicanthus (present) , Autistic behavior (present) , Abnormality of mental function (present)
Geographic origin: Brazil
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Pathogenic
(May 09, 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: SCV002513174.2
First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis … (more)
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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: 27465822, 32827181, 33644862, 27648933, 31785789) (less)
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Pathogenic
(Aug 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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EP300-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004103072.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The EP300 c.3857A>G variant is predicted to result in the amino acid substitution p.Asn1286Ser. This variant has been reported in multiple individuals with Rubinstein-Taybi syndrome … (more)
The EP300 c.3857A>G variant is predicted to result in the amino acid substitution p.Asn1286Ser. This variant has been reported in multiple individuals with Rubinstein-Taybi syndrome and neurodevelopmental disorders; in most of these individuals, this variant was found to have arise de novo (Fergelot et al 2016. PubMed ID: 27648933; Hamilton MJ et al 2016. PubMed ID: 27465822; Table_S2, Turner TN et al 2019. PubMed ID: 31785789; Cross E et al 2020. PubMed ID: 32827181; Hiraide T et al 2021. PubMed ID: 33644862; Hamilton MJ et al 2016. PubMed ID: 27465822). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Feb 26, 2019)
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no assertion criteria provided
Method: literature only
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RUBINSTEIN-TAYBI SYNDROME 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000513411.3
First in ClinVar: Mar 08, 2017 Last updated: Nov 08, 2019 |
Comment on evidence:
By direct sequencing of the EP300 gene in a 2-year-old boy (patient 9) with typical features of Rubinstein-Taybi syndrome-2 (RSTS2; 613684), Hamilton et al. (2016) … (more)
By direct sequencing of the EP300 gene in a 2-year-old boy (patient 9) with typical features of Rubinstein-Taybi syndrome-2 (RSTS2; 613684), Hamilton et al. (2016) identified a de novo heterozygous c.3857A-G transition (c.3857-A-G, NM_001429.3), resulting in an asn1286-to-ser (N1286S) substitution at a highly conserved residue. (less)
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Likely pathogenic
(Nov 05, 2019)
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no assertion criteria provided
Method: clinical testing
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Rubinstein-Taybi syndrome due to EP300 haploinsufficiency
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Wessex Regional Genetics Laboratory, Salisbury District Hospital
Accession: SCV001189992.1
First in ClinVar: Nov 08, 2019 Last updated: Nov 08, 2019 |
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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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Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing. | Hiraide T | Clinical genetics | 2021 | PMID: 33644862 |
Screening of a large Rubinstein-Taybi cohort identified many novel variants and emphasizes the importance of the CREBBP histone acetyltransferase domain. | Cross E | American journal of medical genetics. Part A | 2020 | PMID: 32827181 |
Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations. | Fergelot P | American journal of medical genetics. Part A | 2016 | PMID: 27648933 |
Rubinstein-Taybi syndrome type 2: report of nine new cases that extend the phenotypic and genotypic spectrum. | Hamilton MJ | Clinical dysmorphology | 2016 | PMID: 27465822 |
Text-mined citations for rs1555910821 ...
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.