ClinVar Genomic variation as it relates to human health
NM_006565.4(CTCF):c.1699C>T (p.Arg567Trp)
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_006565.4(CTCF):c.1699C>T (p.Arg567Trp)
Variation ID: 88638 Accession: VCV000088638.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q22.1 16: 67628550 (GRCh38) [ NCBI UCSC ] 16: 67662453 (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 Aug 22, 2016 May 1, 2024 Feb 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006565.4:c.1699C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006556.1:p.Arg567Trp missense NM_001191022.2:c.715C>T NP_001177951.1:p.Arg239Trp missense NM_001363916.1:c.1699C>T NP_001350845.1:p.Arg567Trp missense NC_000016.10:g.67628550C>T NC_000016.9:g.67662453C>T NG_033892.1:g.71144C>T P49711:p.Arg567Trp - Protein change
- R567W, R239W
- Other names
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- Canonical SPDI
- NC_000016.10:67628549:C:T
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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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CTCF | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
261 | 294 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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 (6) |
criteria provided, multiple submitters, no conflicts
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Jul 11, 2023 | RCV000074335.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 3, 2023 | RCV000413282.6 | |
CTCF-related syndromic intellectual disability
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Pathogenic (1) |
criteria provided, single submitter
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Jan 26, 2022 | RCV002260512.3 |
Pathogenic (1) |
criteria provided, single submitter
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Feb 14, 2024 | RCV002399425.2 |
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
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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
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140119.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Aug 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Randwick Genomics Laboratory, Prince of Wales Hospital Sydney, Australia, New South Wales Health Pathology
Accession: SCV001763559.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Sex: female
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Pathogenic
(Dec 21, 2019)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome
Affected status: unknown
Allele origin:
de novo
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002026307.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Pathogenic
(Jan 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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CTCF-related syndromic intellectual disability
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV002540226.1
First in ClinVar: Jul 07, 2022 Last updated: Jul 07, 2022 |
Comment:
The CTCF c.1699C>T (p.Arg567Trp) missense variant results in the substitution of arginine at amino acid position 567 with tryptophan. This variant has been reported in … (more)
The CTCF c.1699C>T (p.Arg567Trp) missense variant results in the substitution of arginine at amino acid position 567 with tryptophan. This variant has been reported in a heterozygous state in at least five individuals with autosomal dominant syndromic intellectual disability (Gregor et al. 2013; Chen et al. 2019; Konrad et al. 2019; Hiraide et al. 2021; Salah et al. 2021). In all cases the variant was reported to have occurred de novo. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant was identified in a de novo state. Based on the available evidence, the c.1699C>T (p.Arg567Trp) variant is classified as pathogenic for CTCF-related syndromic intellectual disability. (less)
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Pathogenic
(Feb 03, 2023)
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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: SCV000491326.4
First in ClinVar: Jan 09, 2017 Last updated: Nov 11, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein … (more)
Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30893510, 28319062, 31239556, 33144682, 33644862, 23746550) (less)
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Pathogenic
(Jul 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome
Affected status: yes
Allele origin:
de novo
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Department of Endocrinology and Genetics, Fuzhou Children’s Hospital of Fujian Medical University
Accession: SCV004012893.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
Sex: female
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Pathogenic
(Feb 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002712444.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R567W pathogenic mutation (also known as c.1699C>T), located in coding exon 7 of the CTCF gene, results from a C to T substitution at … (more)
The p.R567W pathogenic mutation (also known as c.1699C>T), located in coding exon 7 of the CTCF gene, results from a C to T substitution at nucleotide position 1699. The arginine at codon 567 is replaced by tryptophan, an amino acid with dissimilar properties. In one study, this variant was found to be de novo in an individual with severe intellectual disability, autistic features, microcephaly, and severe feeding difficulties. Protein expression studies and molecular modeling suggested no effect on protein expression; however, DNA-binding models suggested a possible decrease in DNA binding affinity and specificity (Gregor A et al. Am. J. Hum. Genet., 2013 Jul;93:124-31). This variant has also been reported as a de novo finding in multiple other individuals with clinical features of CTCF-related neurodevelopmental disorder (Chen F et al. Am J Med Genet C Semin Med Genet, 2019 Jun;181:218-225; Hiraide T et al. Clin Genet, 2021 Jul;100:40-50; Valverde de Morales HG et al. Am J Med Genet A, 2023 Mar;191:718-729). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 11, 2013)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 21
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000105941.4
First in ClinVar: Oct 31, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In a 4-year-old boy with severe intellectual disability with autistic features, microcephaly, and severe feeding difficulties (MRD21; 615502), Gregor et al. (2013) identified a de … (more)
In a 4-year-old boy with severe intellectual disability with autistic features, microcephaly, and severe feeding difficulties (MRD21; 615502), Gregor et al. (2013) identified a de novo c.1699C-T transition (c.1699C-T, NM_006565.3) in the splice donor consensus site of exon 9 of the CTCF gene, resulting in an arg567-to-trp (R567W) substitution. The mutation was not found in the parents, in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, in more than 1,500 in-house exomes, or in 820 healthy controls. A second de novo synonymous variant, 1650C-T, was detected in the same exon on the same allele; in silico analysis showed no evidence for altered splicing, and analysis of patient lymphocytes showed CTCF expression levels similar to those of controls. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome
Affected status: yes
Allele origin:
de novo
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GenomeConnect - Brain Gene Registry
Accession: SCV002107382.1
First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
Comment:
Variant interpreted as Likely pathogenic and reported on 4/11/2016 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient … (more)
Variant interpreted as Likely pathogenic and reported on 4/11/2016 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Abnormality of the face (present) , Global developmental delay (present) , Microcephaly (present) , Growth abnormality (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2016-04-11
Testing laboratory interpretation: Likely pathogenic
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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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Expansion of the genotypic and phenotypic spectrum of CTCF-related disorder guides clinical management: 43 new subjects and a comprehensive literature review. | Valverde de Morales HG | American journal of medical genetics. Part A | 2023 | PMID: 36454652 |
Spectrum of neuro-genetic disorders in the United Arab Emirates national population. | Saleh S | Clinical genetics | 2021 | PMID: 34374989 |
Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing. | Hiraide T | Clinical genetics | 2021 | PMID: 33644862 |
CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum. | Konrad EDH | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31239556 |
Three additional de novo CTCF mutations in Chinese patients help to define an emerging neurodevelopmental disorder. | Chen F | American journal of medical genetics. Part C, Seminars in medical genetics | 2019 | PMID: 30893510 |
De novo mutations in the genome organizer CTCF cause intellectual disability. | Gregor A | American journal of human genetics | 2013 | PMID: 23746550 |
Text-mined citations for rs879255516 ...
HelpRecord last updated May 01, 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.