rs398124146
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_004380.3(CREBBP):c.4336C>T(p.Arg1446Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1446G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004380.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CREBBP | NM_004380.3 | c.4336C>T | p.Arg1446Cys | missense_variant | 26/31 | ENST00000262367.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CREBBP | ENST00000262367.10 | c.4336C>T | p.Arg1446Cys | missense_variant | 26/31 | 1 | NM_004380.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Glioblastoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Gastric adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Medulloblastoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Malignant melanoma of skin Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Rubinstein-Taybi syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 24, 2018 | This sequence change replaces arginine with cysteine at codon 1446 of the CREBBP protein (p.Arg1446Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with polysyndactyly, hirsutism, and clitoromegaly (Invitae). ClinVar contains an entry for this variant (Variation ID: 95047). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Transitional cell carcinoma of the bladder Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of uterine cervix Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 20, 2021 | Variant summary: CREBBP c.4336C>T (p.Arg1446Cys) results in a non-conservative amino acid change located in the CBP/p300-type histone acetyltransferase domain (IPR031162) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251384 control chromosomes (gnomAD). c.4336C>T has been reported in the literature as a somatic mutation in multiple individuals affected with a variety of tumor phenotypes. These reports do not provide unequivocal conclusions about association of the variant with Rubinstein-Taybi Syndrome. However, this variant was previously observed at our laboratory as a de-novo variant in a fetal exome case presenting with increased NT, IUGR, polydactyly, small cerebellum and cardiac anamolies. In addition, one other ClinVar submitter (evaluation after 2014) classified the variant as Likely Pathogenic, citing a de-novo occurrence observed in a sample submitted to their laboratory. These findings suggest a de-novo etiology for disease. At least one publication reports in-vitro experimental evidence showing that the R1446C variant confers a loss-of-function as indicated by reduced acetyltransferase activity in bladder cancer and HEK293 cell lines (e.g. Duex_2018). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Adenoid cystic carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of the large intestine Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell carcinoma of the head and neck Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 11, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at