16-67628550-C-T

Position:

• chr16-67628550-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP5_Very_Strong

The ENST00000264010.10(CTCF):​c.1699C>T​(p.Arg567Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R567L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CTCF ENST00000264010.10 missense, splice_region
• Scores: Splicing: ADA: 0.9981
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 3.49

Genes affected

CTCF (HGNC:13723): (CCCTC-binding factor) This gene is a member of the BORIS + CTCF gene family and encodes a transcriptional regulator protein with 11 highly conserved zinc finger (ZF) domains. This nuclear protein is able to use different combinations of the ZF domains to bind different DNA target sequences and proteins. Depending upon the context of the site, the protein can bind a histone acetyltransferase (HAT)-containing complex and function as a transcriptional activator or bind a histone deacetylase (HDAC)-containing complex and function as a transcriptional repressor. If the protein is bound to a transcriptional insulator element, it can block communication between enhancers and upstream promoters, thereby regulating imprinted expression. Mutations in this gene have been associated with invasive breast cancers, prostate cancers, and Wilms' tumors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CTCF. . Gene score misZ 4.4399 (greater than the threshold 3.09). Trascript score misZ 4.8366 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome.
• PP5: Variant 16-67628550-C-T is Pathogenic according to our data. Variant chr16-67628550-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-67628550-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTCF	NM_006565.4	c.1699C>T	p.Arg567Trp	missense_variant, splice_region_variant	9/12	ENST00000264010.10	NP_006556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTCF	ENST00000264010.10	c.1699C>T	p.Arg567Trp	missense_variant, splice_region_variant	9/12	1	NM_006565.4	ENSP00000264010	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome Pathogenic:6 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	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/. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 11, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP2+PM6+PS4_Supporting+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Endocrinology and Genetics, Fuzhou Children’s Hospital of Fujian Medical University	Jul 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 21, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Randwick Genomics Laboratory, Prince of Wales Hospital Sydney, Australia, New South Wales Health Pathology	Aug 03, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2024

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. -

CTCF-related syndromic intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 26, 2022

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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 03, 2023

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) -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PS2,PS4,PM2,PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;T;.;.;T;T;.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;.;D;.;.;.;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.97	L;L;.;.;L;L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	3.8	N;.;N;.;.;.;.;.
REVEL	Uncertain	0.47
Sift	Benign	0.27	T;.;T;.;.;.;.;.
Sift4G	Uncertain	0.032	D;.;T;.;.;.;.;.
Polyphen		1.0	D;D;.;.;D;D;.;D
Vest4		0.87
MutPred		0.51		Loss of disorder (P = 0.0022);Loss of disorder (P = 0.0022);.;Loss of disorder (P = 0.0022);Loss of disorder (P = 0.0022);Loss of disorder (P = 0.0022);Loss of disorder (P = 0.0022);Loss of disorder (P = 0.0022);
MVP		0.92
MPC		1.8
ClinPred		0.76	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs879255516; hg19: chr16-67662453; COSMIC: COSV50463702; COSMIC: COSV50463702;