ClinVar Miner

Submissions for variant NM_004380.3(CREBBP):c.3779+1G>T

dbSNP: rs587783483
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002536209 SCV003443049 pathogenic Rubinstein-Taybi syndrome 2023-08-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 694820). Disruption of this splice site has been observed in individual(s) with Rubinstein-Taybi syndrome (PMID: 29132461). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 20 of the CREBBP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CREBBP are known to be pathogenic (PMID: 17052327, 18792986).
PreventionGenetics, part of Exact Sciences RCV003413671 SCV004114238 pathogenic CREBBP-related disorder 2022-10-11 criteria provided, single submitter clinical testing The CREBBP c.3779+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been previously reported in individuals with Rubinstein-Taybi syndrome (Li et al. 2017. PubMed ID: 29132461; Cross et al. 2020. PubMed ID: 32827181), and in an individual with developmental disorder (reported with genomic position 3801726 in Table S2, Turner et al. 2019. PubMed ID: 31785789). An alternate nucleotide change (c.3779+1G>A) has also been reported in a large cohort of individuals with Rubinstein-Taibi syndrome (Cross et al. 2020. PubMed ID: 32827181). The c.3779+1G>T variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in CREBBP are expected to be pathogenic. This variant is interpreted as pathogenic.
GeneDx RCV004721656 SCV005327078 pathogenic not provided 2023-08-18 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29132461, 32827181, 31785789)
Wessex Regional Genetics Laboratory, Salisbury District Hospital RCV000856913 SCV000999447 pathogenic Rubinstein-Taybi syndrome due to CREBBP mutations 2019-11-05 no assertion criteria provided clinical testing

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