rs1555534147

Variant names:

• chr16-67611443-CAAAG-C
• rs1555534147
• NM_006565.4:c.615_618delGAAA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006565.4(CTCF):​c.615_618delGAAA​(p.Lys206ProfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTCF NM_006565.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.54
• Publications: 1 publications found

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]

CTCF Gene-Disease associations (from GenCC):

• intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-67611443-CAAAG-C is Pathogenic according to our data. Variant chr16-67611443-CAAAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 521287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTCF	NM_006565.4	c.615_618delGAAA	p.Lys206ProfsTer15	frameshift_variant	Exon 3 of 12	ENST00000264010.10	NP_006556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTCF	ENST00000264010.10	c.615_618delGAAA	p.Lys206ProfsTer15	frameshift_variant	Exon 3 of 12	1	NM_006565.4	ENSP00000264010.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome Pathogenic:4

Mar 04, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS2_VSTR,PS4_MOD,PM2_SUP

Nov 25, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been previously reported as de novo in a similarly affected individual (PMID: 28619046). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000521287 /PMID: 28619046). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with CTCF-related neurodevelopmental disorder (MIM#615502). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least four probands, including proven de novo events; and classified as pathogenic by a diagnostic laboratory in ClinVar (DECIPHER; PMID: 30893510, 31239556) (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Dec 08, 2022

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The heterozygous c.615_618del variant in CTCF has previously been reported in multiple individuals affected with CTCF-related intellectual developmental disorder [PMID:31239556,30893510] and it has been deposited in ClinVar as Pathogenic [ClinVar ID: 521287]. The c.615_618del variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.615_618del variant in CTCF is located in exon 3 of this 12-exon gene, predicted to incorporate a premature translation termination codon [p.(Lys206ProfsTer15)], and is expected to result in loss-of-function via nonsense mediated mRNA decay. Multiple loss-of-function variants that are downstream to the c.615_618del variant have been reported in the literature [PMID: 31239556] and ClinVar [ClinVar ID: 625526] in individuals with CTCF-related disorder. Based on available evidence this de novo c.615_618del p.(Lys206ProfsTer15) variant identified in CTCF gene is classified as Pathogenic

not provided Pathogenic:3

Apr 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36454652, 31239556, 28619046, 30893510)

Jul 08, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 01, 2024

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the CTCF gene demonstrated a 4 base pair deletion in exon 3, c.615_618del. This sequence change results in an amino acid frameshift and creates a premature stop codon 14 amino acids downstream of the change, p.Lys206Profs*15. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CTCF protein with potentially abnormal function. The c.615_618del sequence change has not been described in population databases such as ExAC and gnomAD. This pathogenic sequence change has previously been described in individuals with CTCF-related disorders (PMID: 30893510, 31239556). Collectively, this evidence indicates that this variant is pathogenic.

Inborn genetic diseases Pathogenic:1

Oct 06, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability Pathogenic:1

Oct 04, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1,PS2,PM2

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.5
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1555534147; hg19: chr16-67645346; COSMIC: COSV105852583; COSMIC: COSV105852583;