ClinVar Miner

Submissions for variant NM_001429.3(EP300):c.3857A>G

dbSNP: rs1555910821
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Diagnostic Laboratory, Strasbourg University Hospital RCV001260706 SCV001437798 pathogenic Intellectual disability 2020-09-10 criteria provided, single submitter clinical testing
Invitae RCV000439427 SCV001581591 pathogenic Rubinstein-Taybi syndrome due to EP300 haploinsufficiency 2021-01-29 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has been observed in individual(s) with Rubinstein–Taybi syndrome (PMID: 27648933, 27465822). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 378053). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 1286 of the EP300 protein (p.Asn1286Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine.
Centogene AG - the Rare Disease Company RCV000439427 SCV002028307 likely pathogenic Rubinstein-Taybi syndrome due to EP300 haploinsufficiency 2021-08-30 criteria provided, single submitter clinical testing
GeneDx RCV002244870 SCV002513174 pathogenic not provided 2022-05-09 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27465822, 32827181, 33644862, 27648933, 31785789)
3billion RCV000439427 SCV002521376 pathogenic Rubinstein-Taybi syndrome due to EP300 haploinsufficiency 2022-05-22 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: 0.39). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000378053). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 27465822, 32827181, 33644862). 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 (PMID: 27648933). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002252119 SCV002523993 likely pathogenic See cases 2021-09-03 criteria provided, single submitter clinical testing ACMG classification criteria: PS4, PM2, PM6
Preventiongenetics, part of Exact Sciences RCV003401414 SCV004103072 pathogenic EP300-related condition 2023-08-20 criteria provided, single submitter clinical testing The EP300 c.3857A>G variant is predicted to result in the amino acid substitution p.Asn1286Ser. This variant has been reported in multiple individuals with Rubinstein-Taybi syndrome and neurodevelopmental disorders; in most of these individuals, this variant was found to have arise de novo (Fergelot et al 2016. PubMed ID: 27648933; Hamilton MJ et al 2016. PubMed ID: 27465822; Table_S2, Turner TN et al 2019. PubMed ID: 31785789; Cross E et al 2020. PubMed ID: 32827181; Hiraide T et al 2021. PubMed ID: 33644862; Hamilton MJ et al 2016. PubMed ID: 27465822). 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.
OMIM RCV000439427 SCV000513411 pathogenic Rubinstein-Taybi syndrome due to EP300 haploinsufficiency 2019-02-26 no assertion criteria provided literature only
Wessex Regional Genetics Laboratory, Salisbury District Hospital RCV000439427 SCV001189992 likely pathogenic Rubinstein-Taybi syndrome due to EP300 haploinsufficiency 2019-11-05 no assertion criteria provided clinical testing

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