Submissions for variant NM_006565.4(CTCF):c.1016G>A (p.Arg339Gln)

dbSNP: rs1567610917

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000730247	SCV000857972	uncertain significance	not provided	2018-04-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000730247	SCV001334817	likely pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199945	SCV001370741	likely pathogenic	Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome	2020-05-28	criteria provided, single submitter	clinical testing	Variant summary: CTCF c.1016G>A (p.Arg339Gln) results in a conservative amino acid change located in the zinc finger 3, C2H2-type domain (IPR013087) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD) (PM2). c.1016G>A has been reported in the literature as a de novo occurrence in one proband (clinical exome trio testing) with symptoms including intrauterine growth restriction, failure to thrive and hypotonia and no family history (Konrad_2019) (PS2). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nevertheless, Arg339 in ZF3 is found to form hydrogen bonds within the core sequence of CTCF-binding conserved sequence elements in the promoter region of members of different mammalian gene clusters (Yin_2017); this provides evidence for the potential importance of this codon to protein function. A ClinVar submitter (evaluation in 2018) cites the variant as uncertain significance. Based on the evidence outlined above (ACMG criteria PS2 and PM2), the variant was classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001199945	SCV002026294	likely pathogenic	Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome	2019-12-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000730247	SCV002031044	pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Bailey et al., 2021); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31239556, 29076501, 33004838, 34657170)
Invitae	RCV000730247	SCV002956893	pathogenic	not provided	2021-12-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CTCF function (PMID: 34657170). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 594856). This missense change has been observed in individual(s) with clinical features of CTCF-related conditions (PMID: 31239556, 33004838). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 339 of the CTCF protein (p.Arg339Gln).
Illumina Laboratory Services, Illumina	RCV001199945	SCV004014739	pathogenic	Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome	2023-04-11	criteria provided, single submitter	clinical testing	The CTCF c.1016G>A (p.Arg339Gln) missense variant results in the substitution of arginine at amino acid position 339 with glutamine. Across a selection of the available literature, this variant has been reported in at least six unrelated individuals with features of a neurodevelopmental disorder, including in a de novo state (PMID: 31239556; PMID: 36454652). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies have demonstrated that this variant, which is located within the third zinc finger domain and affects a key DNA-contacting residue, alters the function of the protein (PMID: 34657170; PMID: 29076501). This variant occurred in a de novo state. Based on the available evidence, the c.1016G>A (p.Arg339Gln) variant is classified as pathogenic for intellectual developmental disorder.