ClinVar Miner

Submissions for variant NM_004380.3(CREBBP):c.4336C>T (p.Arg1446Cys) (rs398124146)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081052 SCV000112959 uncertain significance not provided 2013-06-11 criteria provided, single submitter clinical testing
Invitae RCV000700948 SCV000829727 likely pathogenic Rubinstein-Taybi syndrome 1 2018-04-27 criteria provided, single submitter clinical testing 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.
Integrated Genetics/Laboratory Corporation of America RCV000700948 SCV001363075 likely pathogenic Rubinstein-Taybi syndrome 1 2019-06-20 criteria provided, single submitter clinical testing 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 (ACMG PP3). The variant was absent in 251384 control chromosomes (ACMG PM2). c.4336C>T has been reported in the literature as a somatic variant in individuals affected with a variety of tumors. These report(s) do not provide unequivocal conclusions about association of the variant with Rubinstein-Taybi syndrome. This variant was observed at our laboratory as a de-novo variant in one fetal exome case presenting with increased NT, IUGR, polydactyly, small cerebellum and cardiac anamolies. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported although at-least one study reports that another variant at this codon (p.R1446L) resulted in reduced HAT (Histone Acetyltransferase) activity in-vitro supporting a role for loss of HAT activity of CREBBP in human SHH MB (Sonic Hedgehog Medulloblastoma) (Merk_2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic citing a de-novo occurrence. This variant was initially reported as a VUS, however emerging evidence from the ClinVar submitting laboratory coupled with ours points to a de-novo etiology (ACMG PS2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Database of Curated Mutations (DoCM) RCV000441267 SCV000505935 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423556 SCV000505936 likely pathogenic Uterine cervical neoplasms 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434703 SCV000505937 likely pathogenic Adenoid cystic carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443206 SCV000505938 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426447 SCV000505939 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433226 SCV000505940 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442404 SCV000505941 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426681 SCV000505942 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436055 SCV000505943 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418574 SCV000505944 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425760 SCV000505945 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only

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