NM_004380.3(CREBBP):c.6250C>T (p.Gln2084Ter) AND Rubinstein-Taybi syndrome due to CREBBP mutations

Germline classification:: Likely pathogenic (2 submissions)
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001265550.2

Allele description [Variation Report for NM_004380.3(CREBBP):c.6250C>T (p.Gln2084Ter)]

NM_004380.3(CREBBP):c.6250C>T (p.Gln2084Ter)

Gene:

CREBBP:CREB binding protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_004380.3(CREBBP):c.6250C>T (p.Gln2084Ter)

HGVS:

NC_000016.10:g.3728797G>A
NG_009873.2:g.156917C>T
NM_001079846.1:c.6136C>T
NM_004380.3:c.6250C>TMANE SELECT
NP_001073315.1:p.Gln2046Ter
NP_004371.2:p.Gln2084Ter
LRG_1426t1:c.6250C>T
LRG_1426:g.156917C>T
LRG_1426p1:p.Gln2084Ter
NC_000016.9:g.3778798G>A
NG_009873.1:g.156324C>T
NM_004380.2:c.6250C>T

Protein change:

Q2046*

Links:

dbSNP: rs2051825168

NCBI 1000 Genomes Browser:

rs2051825168

Molecular consequence:

NM_001079846.1:c.6136C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004380.3:c.6250C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Rubinstein-Taybi syndrome due to CREBBP mutations
Synonyms:: Rubinstein syndrome; Broad thumbs and great toes, characteristic facies, and mental retardation; RUBINSTEIN-TAYBI SYNDROME 1, INCOMPLETE; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008393; MedGen: C4551859; Orphanet: 783; OMIM: 180849

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001443702	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004013792	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001443702

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004013792

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001443702.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This nonsense mutation is found in the last exon of CREBBP and it is therefore predicted to escape nonsense-mediated mRNA decay (NMD). However, the last exon of this gene is large and nonsense/frameshift mutations located downstream of this variant have been reported as disease-causing variants in the Human Gene Mutation Database (PMID: 15706485, 18792986, 25388907). This variant has not been previously reported or functionally characterized in the literature to our knowledge. It is absent from the gnomAD population database and thus is presumed to be rare. The c.6250C>T (p.Gln2084Ter) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. 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, the c.6250C>T (p.Gln2084Ter) variant is classified as Pathogenic

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV004013792.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with CREBBP related disorder (ClinVar ID: VCV000984922). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jul 22, 2023

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