ClinVar Genomic variation as it relates to human health
NM_004380.3(CREBBP):c.5602C>T (p.Arg1868Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004380.3(CREBBP):c.5602C>T (p.Arg1868Trp)
Variation ID: 265346 Accession: VCV000265346.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 3729445 (GRCh38) [ NCBI UCSC ] 16: 3779446 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 7, 2017 Jul 15, 2024 Apr 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004380.3:c.5602C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004371.2:p.Arg1868Trp missense NM_001079846.1:c.5488C>T NP_001073315.1:p.Arg1830Trp missense NC_000016.10:g.3729445G>A NC_000016.9:g.3779446G>A NG_009873.2:g.156269C>T LRG_1426:g.156269C>T LRG_1426t1:c.5602C>T LRG_1426p1:p.Arg1868Trp - Protein change
- R1868W, R1830W
- Other names
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- Canonical SPDI
- NC_000016.10:3729444:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CREBBP | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2203 | 2314 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2020 | RCV000254930.23 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 20, 2023 | RCV000757967.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 15, 2022 | RCV002282094.2 | |
See cases
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Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2022 | RCV003156089.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 15, 2019)
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criteria provided, single submitter
Method: clinical testing
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Menke-Hennekam syndrome 1
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429016.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 02, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000322143.7
First in ClinVar: Oct 10, 2016 Last updated: Apr 17, 2019 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29460469, 30892814, 27311832, 29159939) (less)
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Pathogenic
(Jul 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Menke-Hennekam syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002570768.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: CREBBP c.5602C>T (p.Arg1868Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: CREBBP c.5602C>T (p.Arg1868Trp) results in a non-conservative amino acid change in 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 250920 control chromosomes. c.5602C>T has been reported in the literature as a de-novo variant in multiple individuals with CREBBP-related disorders lacking the characteristic facial and limb dysmorphism associated with RubinsteinTaybi syndrome (RTS), specifically called as Menke-Hennekam syndrome (example, Menke_2018, Banka_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500054.20
First in ClinVar: Mar 14, 2021 Last updated: Jul 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
unknown
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Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV003845234.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Clinical Features:
2-3 toe syndactyly (present) , Abnormality of the dentition (present) , Brachycephaly (present) , Brachydactyly (present) , Coarse facial features (present) , Dental malocclusion (present) … (more)
2-3 toe syndactyly (present) , Abnormality of the dentition (present) , Brachycephaly (present) , Brachydactyly (present) , Coarse facial features (present) , Dental malocclusion (present) , Downturned corners of mouth (present) , Dysplastic corpus callosum (present) , High forehead (present) , Hirsutism (present) , Intellectual disability (present) , Intellectual disability, profound (present) , Long philtrum (present) , Low-set ears (present) , Mandibular prognathia (present) , Microcephaly (present) , Narrow palate (present) , Overfolding of the superior helices (present) , Pes planus (present) , Retinal detachment (present) , Scoliosis (present) , Seizure (present) , Short stature (present) , Short thumb (present) , Synophrys (present) , Thin upper lip vermilion (present) , Wide nasal bridge (present) (less)
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Pathogenic
(Apr 20, 2023)
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criteria provided, single submitter
Method: research
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Menke-Hennekam syndrome 1
Affected status: yes
Allele origin:
de novo
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Duke University Health System Sequencing Clinic, Duke University Health System
Accession: SCV003918951.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Menke-Hennekam syndrome 1
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV004013688.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000265346 / PMID: 27311832) and a different missense change at the same codon (p.Arg1868Gln / ClinVar ID: VCV000598959 / PMID: 29460469) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Poor suck (present) , Recurrent lower respiratory tract infections (present) , Abnormal facial shape (present) , Microphthalmia (present) , Upslanted … (more)
Global developmental delay (present) , Poor suck (present) , Recurrent lower respiratory tract infections (present) , Abnormal facial shape (present) , Microphthalmia (present) , Upslanted palpebral fissure (present) , Failure to thrive (present) , Low-set ears (present) , Long philtrum (present) , Hearing impairment (present) , Abnormal foot morphology (present) , Pectus excavatum (present) , Inguinal hernia (present) , Cryptorchidism (present) (less)
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Pathogenic
(Feb 22, 2019)
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no assertion criteria provided
Method: literature only
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MENKE-HENNEKAM SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000886492.1
First in ClinVar: Feb 25, 2019 Last updated: Feb 25, 2019 |
Comment on evidence:
In 2 unrelated girls (patients 9 and 10) with Menke-Hennekam syndrome-1 (MKHK1; 618332), Menke et al. (2016) detected heterozygosity for a C-to-T transition at nucleotide … (more)
In 2 unrelated girls (patients 9 and 10) with Menke-Hennekam syndrome-1 (MKHK1; 618332), Menke et al. (2016) detected heterozygosity for a C-to-T transition at nucleotide 5602 (c.5602C-T, GRCh37) in exon 31 of the CREBBP gene, resulting in an atg1868-to-trp (R1868W) substitution. This de novo mutation was not present in the ESP or ExAC databases. Menke et al. (2018) found the R1868W mutation (c.5602C-T, NM_004380.2) in 3 unrelated children (patients C17, C18, and C19) with MKHK1. The mutation occurred de novo in all 3 cases and was not found in gnomAD. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genotype-phenotype specificity in Menke-Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP. | Banka S | American journal of medical genetics. Part A | 2019 | PMID: 30892814 |
Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome. | Menke LA | American journal of medical genetics. Part A | 2018 | PMID: 29460469 |
Marked yield of re-evaluating phenotype and exome/target sequencing data in 33 individuals with intellectual disabilities. | Xiao B | American journal of medical genetics. Part A | 2018 | PMID: 29159939 |
CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype. | Menke LA | American journal of medical genetics. Part A | 2016 | PMID: 27311832 |
Text-mined citations for rs886039491 ...
HelpRecord last updated Jul 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.