Submissions for variant NM_004380.3(CREBBP):c.5614A>G (p.Met1872Val)

dbSNP: rs797045037

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191076	SCV000245468	likely pathogenic	Rubinstein-Taybi syndrome due to CREBBP mutations	2013-05-16	criteria provided, single submitter	clinical testing	Likely pathogenicity based on finding it once in our laboratory de novo in a 20-year-old female with intellectual disability, epilepsy, anxiety. She also had a de novo variant in an epilepsy-associated gene.
GeneDx	RCV000523539	SCV000616692	pathogenic	not provided	2022-12-04	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; This variant is associated with the following publications: (PMID: 26942292, 27311832, 29460469, 34652060)
Diagnostic Laboratory, Strasbourg University Hospital	RCV001260745	SCV001437837	pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517032	SCV003441815	pathogenic	Rubinstein-Taybi syndrome	2023-07-01	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 209145). This missense change has been observed in individual(s) with clinical features of Menke-Hennekam syndrome (PMID: 27311832, 29460469). In at least one individual the variant was observed to be de novo. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1872 of the CREBBP protein (p.Met1872Val).
Revvity Omics, Revvity	RCV003458352	SCV003830005	likely pathogenic	Rubinstein-Taybi syndrome due to CREBBP mutations; Menke-Hennekam syndrome 1	2024-03-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003422092	SCV004117107	pathogenic	CREBBP-related disorder	2022-09-14	criteria provided, single submitter	clinical testing	The CREBBP c.5614A>G variant is predicted to result in the amino acid substitution p.Met1872Val. This variant has been previously reported as a recurrent de novo variant in individuals with variable developmental delay, intellectual disability, short stature and/or microcephaly (see for example Menke et al. 2016. PubMed ID: 27311832; Menke et al. 2018. PubMed ID: 29460469; Patient 2, Table 1, Nishi et al. 2022. PubMed ID: 34652060). 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	RCV000757968	SCV000886493	pathogenic	Menke-Hennekam syndrome 1	2019-02-22	no assertion criteria provided	literature only
GenomeConnect - Brain Gene Registry	RCV003458352	SCV004176862	not provided	Rubinstein-Taybi syndrome due to CREBBP mutations; Menke-Hennekam syndrome 1		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 01-23-2023 by PreventionGenetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.