ClinVar Miner

Submissions for variant NM_004380.3(CREBBP):c.4133G>C (p.Arg1378Pro)

dbSNP: rs121434626
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Provincial Medical Genetics Program of British Columbia, University of British Columbia RCV000010037 SCV002320825 likely pathogenic Rubinstein-Taybi syndrome due to CREBBP mutations 2022-01-01 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV005249986 SCV005900533 likely pathogenic CREBBP-related disorder 2024-02-19 criteria provided, single submitter clinical testing The CREBBP gene is constrained against variation (Z-score= 4.76 and pLI = 1). The c.4133G>C (p.Arg1378Pro) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Multiple splice prediction tools also suggest that this variant is likely to interfere with normal splicing. This variant has been previously reported as a heterozygous change in patients with autosomal dominant Rubinstein-Taybi syndrome (PMID: 11331617, 25388907). Functional studies indicate this variant leads to reduced histone acetyltransferase activity (PMID: 11331617). The c.4133G>C (p.Arg1378Pro) variant is absent from the gnomAD v4 population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, c.4133G>C (p.Arg1378Pro) is classified as Likely Pathogenic.
OMIM RCV000010037 SCV000030258 pathogenic Rubinstein-Taybi syndrome due to CREBBP mutations 2001-05-01 no assertion criteria provided literature only

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