VCV002978296.2 - ClinVar

NM_001429.4(EP300):c.6787C>T (p.Arg2263Ter)

Germline

Classification

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.

(2)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001429.4(EP300):c.6787C>T (p.Arg2263Ter)

Variation ID: 2978296 Accession: VCV002978296.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.2 22: 41178498 (GRCh38) [ NCBI UCSC ] 22: 41574502 (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	Feb 29, 2024	Oct 8, 2024	Jul 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001429.4:c.6787C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001420.2:p.Arg2263Ter	nonsense
NM_001362843.2:c.6709C>T	NP_001349772.1:p.Arg2237Ter	nonsense
NM_001429.3:c.6787C>T
NC_000022.11:g.41178498C>T
NC_000022.10:g.41574502C>T
NG_009817.1:g.90889C>T
LRG_1422:g.90889C>T
LRG_1422t1:c.6787C>T	LRG_1422p1:p.Arg2263Ter

... more HGVS ... less HGVS

Protein change

R2263*, R2237*

Other names

Canonical SPDI

NC_000022.11:41178497:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

VarSome

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
Gene	OMIM	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.
EP300		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1784	1935

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.
Rubinstein-Taybi syndrome due to EP300 haploinsufficiency	Pathogenic (1)	criteria provided, single submitter	Jan 28, 2023	RCV003836958.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jul 20, 2023	RCV004723511.1

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 (Jan 28, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004637454.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 17299436‚ 33084842 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the EP300 protein in which other variant(s) (p.Pro2367Argfs36) have … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the EP300 protein in which other variant(s) (p.Pro2367Argfs36) have been determined to be pathogenic (PMID: 17299436). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with congenital heart disease (PMID: 33084842). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2263*) in the EP300 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 152 amino acid(s) of the EP300 protein. (less)
Likely pathogenic (Jul 20, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005333458.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: Identified in an individual with congenital heart disease; detailed clinical and segregation information was nor reported (Morton SU et al., 2021); Not observed at significant … (more) Identified in an individual with congenital heart disease; detailed clinical and segregation information was nor reported (Morton SU et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 152 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 33084842) (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the EP300 protein in which other variant(s) (p.Pro2367Argfs*36) have been determined to be pathogenic (PMID: 17299436). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with congenital heart disease (PMID: 33084842). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2263*) in the EP300 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 152 amino acid(s) of the EP300 protein.

Comment:

Identified in an individual with congenital heart disease; detailed clinical and segregation information was nor reported (Morton SU et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 152 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 33084842)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart Disease.	Morton SU	JAMA cardiology	2021	PMID: 33084842
Confirmation of EP300 gene mutations as a rare cause of Rubinstein-Taybi syndrome.	Zimmermann N	European journal of human genetics : EJHG	2007	PMID: 17299436

Text-mined citations for this variant ...

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001429.4(EP300):c.6787C>T (p.Arg2263Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...