Submissions for variant NM_006565.4(CTCF):c.1699C>T (p.Arg567Trp)

dbSNP: rs879255516

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413282	SCV000491326	pathogenic	not provided	2023-02-03	criteria provided, single submitter	clinical testing	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)
Mendelics	RCV000074335	SCV001140119	pathogenic	Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Randwick Genomics Laboratory, Prince of Wales Hospital Sydney, Australia, New South Wales Health Pathology	RCV000074335	SCV001763559	pathogenic	Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome	2021-08-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000074335	SCV002026307	pathogenic	Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome	2019-12-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV002260512	SCV002540226	pathogenic	CTCF-related syndromic intellectual disability	2022-01-26	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002399425	SCV002712444	pathogenic	Inborn genetic diseases	2024-02-14	criteria provided, single submitter	clinical testing	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.
Department of Endocrinology and Genetics, Fuzhou Children’s Hospital of Fujian Medical University	RCV000074335	SCV004012893	pathogenic	Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome	2023-07-11	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000074335	SCV005418082	likely pathogenic	Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PP2+PM6+PS4_Supporting+PP4
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798770	SCV005420471	pathogenic	Intellectual disability	2024-10-04	criteria provided, single submitter	research	PS2,PS4,PM2,PP3
OMIM	RCV000074335	SCV000105941	pathogenic	Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome	2013-07-11	no assertion criteria provided	literature only
GenomeConnect - Brain Gene Registry	RCV000074335	SCV002107382	not provided	Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome		no assertion provided	phenotyping only	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/.