22-41176250-T-G

Variant names:

• chr22-41176250-T-G
• rs1057517732
• NM_001429.4:c.4783T>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001429.4(EP300):​c.4783T>G​(p.Phe1595Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1595I) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EP300 NM_001429.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 8.02
• Publications: 2 publications found

Genes affected

EP300 (HGNC:3373): (E1A binding protein p300) This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein. It functions as histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and thus plays a role in the stimulation of hypoxia-induced genes such as VEGF. Defects in this gene are a cause of Rubinstein-Taybi syndrome and may also play a role in epithelial cancer. [provided by RefSeq, Jul 2008]

EP300-AS1 (HGNC:50504): (EP300 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-41176250-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1685771.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 22-41176250-T-G is Pathogenic according to our data. Variant chr22-41176250-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001429.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EP300	NM_001429.4	MANE Select	c.4783T>G	p.Phe1595Val	missense	Exon 30 of 31	NP_001420.2
	EP300	NM_001362843.2		c.4705T>G	p.Phe1569Val	missense	Exon 29 of 30	NP_001349772.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EP300	ENST00000263253.9	TSL:1 MANE Select	c.4783T>G	p.Phe1595Val	missense	Exon 30 of 31	ENSP00000263253.7
	EP300	ENST00000715703.1		c.4783T>G	p.Phe1595Val	missense	Exon 30 of 31	ENSP00000520505.1
	EP300	ENST00000674155.1		c.4705T>G	p.Phe1569Val	missense	Exon 29 of 30	ENSP00000501078.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Pathogenic:9

Jun 21, 2019

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1595 of the EP300 protein (p.Phe1595Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Rubinstein-Taybi syndrome (PMID: 27465822, 29133209). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 372363). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EP300 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Apr 15, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant. The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372363 / PMID: 26633542 / 3billion dataset). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27465822). 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 (3billion dataset). A different missense change at the same codon (p.Phe1595Ile) has been reported to be associated with EP300-related disorder (ClinVar ID: VCV001685771). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Feb 20, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM2, PP3, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 372363). This variant has been previously reported as causative for EP300-related l disorders (PMID:29133209).

Feb 26, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Rubinstein-Taybi syndrome 2 (RSTS; MIM#613684) and Menke-Hennekam syndrome 2 (MHS2; MIM#618333). Additionally, dominant negative is a suggested mechanism (PMIDs: 20301699, 24381114). Variants reported to cause RSTS are found throughout the protein, whereas of the few variants reported to cause MHS, all were located in exon 31 (PMID: 29460469). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical features and developmental outcomes vary considerably between individuals with RSTS, with rare reports of pathogenic variants inherited from asymptomatic or mildly affected parents (PMID: 20301699). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to valine. (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) 0600 - Variant is located in the annotated histone acetylation protein (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and likely pathogenic, and has been observed in individuals with Rubinstein-Taybi syndrome. In at least two of these individuals, the variant was confirmed de novo (ClinVar, PMID: 29133209). (SP) 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

Dec 11, 2017

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 02, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in EP300 is predicted to replace phenylalanine with valine at codon 1595, p.(Phe1595Val). The phenylalanine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the HAT domain. There is a small physicochemical difference between phenylalanine and valine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.0002% (2/1,112,006 alleles) in the European (non-Finnish) population. This variant has been identified as a de novo occurrence with confirmed parental relationships in five individuals with syndromic intellectual disability (PMID: 26633542, 27465822, 29133209, 36973392; Shariant). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.953). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS2_VeryStrong, PP3_Moderate, PM2_Supporting.

Apr 15, 2025

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EP300 c.4783T>G (p.Phe1595Val) variant has been reported in four individuals with Rubinstein-Taybi Syndrome and has been identified as occurring de novo in all of them (Costain G et al., PMID: 29133209; Hamilton MJ et al., PMID: 27465822; Lecoquierre F et al., PMID: 31036916; Welters A et al., PMID: 31137009). This variant has been reported in the ClinVar database as a pathogenic variant by ten submitters, as a likely pathogenic variant by three submitters, and as a variant of uncertain significance by one submitter (Variation ID: 372363). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to EP300 function. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

not provided Pathogenic:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 09, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A pathogenic variant has been identified in the EP300 gene. The F1595V variant has been identified as a de novo variant with confirmed parentage in multiple unrelated individuals with developmental delay and dysmorphic features who were previously tested at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F1595V variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts the F1595V variant is probably damaging to the protein structure/function. Therefore, the presence of this pathogenic variant is consistent with a diagnosis of Rubinstein-Taybi syndrome

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 31, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Pathogenic:1

Oct 02, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EP300-related disorder Pathogenic:1

Oct 10, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EP300 c.4783T>G variant is predicted to result in the amino acid substitution p.Phe1595Val. This variant was reported to be a de novo event in multiple individuals with Rubinstein–Taybi syndrome (Table S3 - Retterer et al. 2016. PubMed ID: 26633542; Hamilton et al. 2016. PubMed ID: 27465822; Costain et al. 2017. PubMed ID: 29133209; Lecoquierre et al. 2019. PubMed ID: 31036916; Welters et al. 2019. PubMed ID: 31137009). 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.

Multiple congenital anomalies Other:1

Costain lab, The Hospital for Sick Children

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.62		Gain of sheet (P = 0.0827)
MVP		0.95
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.92
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057517732; hg19: chr22-41572254;