ClinVar Miner

Submissions for variant NM_001429.4(EP300):c.6662C>T (p.Pro2221Leu)

gnomAD frequency: 0.00004  dbSNP: rs28937578
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV003418785 SCV004117381 uncertain significance EP300-related disorder 2023-07-05 criteria provided, single submitter clinical testing The EP300 c.6662C>T variant is predicted to result in the amino acid substitution p.Pro2221Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-41574377-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp RCV005062903 SCV005717195 uncertain significance Rubinstein-Taybi syndrome due to EP300 haploinsufficiency 2024-07-03 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2221 of the EP300 protein (p.Pro2221Leu). This variant is present in population databases (rs28937578, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with EP300-related conditions. ClinVar contains an entry for this variant (Variation ID: 2634694). 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 not expected to disrupt EP300 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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