ClinVar Genomic variation as it relates to human health

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

The variant has been previously reported as de novoo in a similarly affected individual (PMID: 27465822, PS2) The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.953, 3Cnet: 0.763, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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.

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.

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

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).