ClinVar

Description

The c.4409A>G (p.H1470R) alteration is located in exon 27 (coding exon 27) of the CREBBP gene. This alteration results from a A to G substitution at nucleotide position 4409, causing the histidine (H) at amino acid position 1470 to be replaced by an arginine (R). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the CREBBP c.4409A>G alteration was not observed among 6,497 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The amino acid change has been observed in affected individuals: _x000D_ This missense alteration has been previously reported in one individual with a clinical diagnosis of RSTS (Roelfsema, 2005). No parental samples were available to determine inheritance status. The altered amino acid is conserved throughout evolution:_x000D_ The p.H1470 amino acid is completely conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ The p.H1470R amino acid is located in the highly-conserved histone acetyl transferase (HAT) domain, which is important in the regulation of transcription. Within the HAT domain of CBP, two functionally important regions have been identified. One of these regions (amino acids 1459–1541) is postulated to be the coenzyme A (CoA) binding site (Kalkhoven, 2003). Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ Functional analysis of a missense alteration at the corrsponding position in the mouse CBP protein (H1471) demonstrated a reduction in histone acetyltransferase activity and activation potential (Martinez-Balbas, 1998). The alteration is predicted deleterious by in silico models:_x000D_ The p.H1470R alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as pathogenic.