ClinVar Miner

Submissions for variant NM_004380.3(CREBBP):c.3641A>G (p.Tyr1214Cys)

gnomAD frequency: 0.00001  dbSNP: rs1272691121
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001663140 SCV001872484 uncertain significance not provided 2023-02-22 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; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002495982 SCV002775803 uncertain significance Rubinstein-Taybi syndrome due to CREBBP mutations; Menke-Hennekam syndrome 1 2021-10-20 criteria provided, single submitter clinical testing
Molecular Genetics, Royal Melbourne Hospital RCV003994317 SCV004812556 uncertain significance Rubinstein-Taybi syndrome due to CREBBP mutations 2022-03-03 criteria provided, single submitter clinical testing This sequence change in CREBBP is predicted to replace tyrosine with cysteine at codon 1214, p.(Tyr1214Cys). The tyrosine residue is highly conserved (100 vertebrates, UCSC), and is located in a Cys/His rich region. There is a large physicochemical difference between tyrosine and cysteine. The highest population minor allele frequency in gnomAD v3.1 (absent in gnomAD v2.1) is 0.005% (2/41,436 alleles) in the African/African American population. To our knowledge, this variant has not been reported in the literature in any individuals with CREBBP-related conditions. The variant has been reported as a variant of uncertain significance (ClinVar ID: 1253583). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.
PreventionGenetics, part of Exact Sciences RCV004743559 SCV005344443 uncertain significance CREBBP-related disorder 2024-03-20 no assertion criteria provided clinical testing The CREBBP c.3641A>G variant is predicted to result in the amino acid substitution p.Tyr1214Cys. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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