Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000433287 | SCV000524379 | likely pathogenic | not provided | 2016-03-04 | criteria provided, single submitter | clinical testing | The M1588T variant in the EP300 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The M1588T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M1588T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. The M1588T variant is a strong candidate for a pathogenic variant. |
Hudson |
RCV000454987 | SCV000540909 | pathogenic | Rubinstein-Taybi syndrome due to EP300 haploinsufficiency | 2017-03-09 | criteria provided, single submitter | research | |
Invitae | RCV000454987 | SCV001225158 | pathogenic | Rubinstein-Taybi syndrome due to EP300 haploinsufficiency | 2019-12-12 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with clinical features of EP300-related conditions (PMID: 30076641, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 383803). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 1588 of the EP300 protein (p.Met1588Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. For these reasons, this variant has been classified as Pathogenic. 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. |