Submissions for variant NM_004380.3(CREBBP):c.1369A>G (p.Ile457Val)

gnomAD frequency: 0.00009  dbSNP: rs369459749

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081029	SCV000112936	uncertain significance	not provided	2015-06-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000081029	SCV001899736	benign	not provided	2020-09-18	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002265601	SCV002548661	uncertain significance	Rubinstein-Taybi syndrome due to CREBBP mutations	2021-07-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381401	SCV002702236	uncertain significance	Inborn genetic diseases	2018-01-25	criteria provided, single submitter	clinical testing	The p.I457V variant (also known as c.1369A>G), located in coding exon 6 of the CREBBP gene, results from an A to G substitution at nucleotide position 1369. The isoleucine at codon 457 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514423	SCV003237528	uncertain significance	Rubinstein-Taybi syndrome	2023-05-25	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with CREBBP-related conditions. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 457 of the CREBBP protein (p.Ile457Val). This variant is present in population databases (rs369459749, gnomAD 0.008%). ClinVar contains an entry for this variant (Variation ID: 95024). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CREBBP protein function. 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.
PreventionGenetics, part of Exact Sciences	RCV004742248	SCV005350909	likely benign	CREBBP-related disorder	2021-10-09	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).