Submissions for variant NM_001429.4(EP300):c.5245C>T (p.Arg1749Trp)

dbSNP: rs2145515250

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002273562	SCV002558411	uncertain significance	not provided	2022-06-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471273	SCV002769132	likely pathogenic	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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 (GeneReviews, PMID: 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 (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3; p.(Arg1749Gln), 1 heterozygote). (I) 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 zf-TAZ domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. The variant has been previously classified as a VUS (LOVD). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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
PreventionGenetics, part of Exact Sciences	RCV004729129	SCV005338153	uncertain significance	EP300-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The EP300 c.5245C>T variant is predicted to result in the amino acid substitution p.Arg1749Trp. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.