CITED2

protein-coding

Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2

Gene summary

The protein encoded by this gene inhibits transactivation of HIF1A-induced genes by competing with binding of hypoxia-inducible factor 1-alpha to p300-CH1. Mutations in this gene are a cause of cardiac septal defects. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

MANE transcript

NM_006079.5

Inheritance

ClinVar variants

P:1U:65B:14

Top phenotype

Atrial septal defect 8; Ventricular septal defect 2

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr6:139,371,807-139,374,648

External References & Databases

Ensembl (ENSG00000164442)

Transcript & Mutation Effects

hg38 • Region Span ~2.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart defects, multiple typesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0000119

Submitter: Ambry Genetics

ventricular septal defect 2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013748

Submitter: Labcorp Genetics (formerly Invitae)

congenital heart diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*CITED2* was first reported in relation to autosomal dominant congenital heart disease in 2012 (Chen et al., PMID 23082118). At least 10 rare variants (9 missense, 1 splice variant in the non-canonical gene) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. *CITED2* has been noted to be associated with the following disease entities: atrial septal defect and ventricular septal defect (OMIM 614431 and 614433). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, these disease entities have been lumped into one disease entity, Autosomal Dominant *CITED2*-related Congenital Heart Disorders. Variants in this gene have been reported in at least 10 probands in 10 publications (PMIDs 23082118, 24848765, 24456003, 28436679, 28687891, 31515672), using an allele frequency threshold of 1x10-5. This gene-disease relationship is supported by animal models, expression studies, and functional assays. Expression studies confirmed that *CITED2* is expressed early in chick and mouse embryogenesis (PMIDs 11044621, 11823447, 15750185, 17133411). Fetal human tissues from hearts affected by ventricular septal defects had decreased *CITED2* expression (PMID 23899608). Loss of *CITED2* resulted in impaired mesoderm and cardiomyocyte differentiation from mouse embryonic stem cells (PMIDs 22761414, 31378782), while overexpression led to increased cardiac differentiation (PMID 27818139). Mouse models demonstrated that deficiency of *Cited2* led to cardiac malformations as well as neural tube defects (PMIDs 15475956, 12149478, 11694877, 15750185, 18440989, 21224256, 22504313). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 9/5/23 (SOP Version 9).

atrial septal defect 8MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013750

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Atrial septal defect 8; Ventricular septal defect 2AD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: The conditions may involve congenital cardiac anomalies, and awareness may allow early diagnosis and interventions

Comments: Variants may be involved in Premature ovarian failure (AD), but the evidence is unclear

Refs: 16287139; 20654020; 22709740; 23082118

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CITED2 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 41

not providedTotal: 36

CITED2-related disorderTotal: 16

not specifiedTotal: 12

Atrial septal defect 8Total: 5

Ventricular septal defect 2Total: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006079.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				8 clinvar	3 clinvar	11
missense		1 clinvar	63 clinvar	3 clinvar		67
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	1	65	11	3	80

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006079.5	RefSeq	NP_006070.2	1	MANE Select
ENST00000367651.4	Ensembl	ENSP00000356623.2	1	MANE Select
NM_001168388.3	RefSeq	NP_001161860.1	1	Standard
NM_001168389.3	RefSeq	NP_001161861.2	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mitophagy - animal - Homo sapiens (human)
Gene expression (Transcription)
mechanism of gene regulation by peroxisome proliferators via ppara
Generic Transcription Pathway
RNA Polymerase II Transcription

Biological Process

negative regulation of transcription by RNA polymerase II
response to hypoxia
liver development
outflow tract morphogenesis
regulation of animal organ formation

Molecular Function

chromatin binding
DNA-binding transcription factor activity
transcription coactivator activity
transcription corepressor activity
protein binding

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367651
Coding exons: 1
Length: 2365
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.474	179	162	1.10	0.00000745	1833
Missense (PolyPhen)		60	58.432	1.0268		717
Synonymous	-4.72	111	63.2	1.76	0.00000315	499
Loss of Function	2.02	0	4.76	0.00	2.13e-7	43

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional coactivator of the p300/CBP-mediated transcription complex. Acts as a bridge, linking TFAP2 transcription factors and the p300/CBP transcriptional coactivator complex in order to stimulate TFAP2-mediated transcriptional activation. Positively regulates TGF-beta signaling through its association with the SMAD/p300/CBP-mediated transcriptional coactivator complex. Stimulates the peroxisome proliferator- activated receptors PPARA transcriptional activity. Enhances estrogen-dependent transactivation mediated by estrogen receptors. Acts also as a transcriptional corepressor; interferes with the binding of the transcription factors HIF1A or STAT2 and the p300/CBP transcriptional coactivator complex. Participates in sex determination and early gonad development by stimulating transcription activation of SRY. Plays a role in controlling left- right patterning during embryogenesis; potentiates transcriptional activation of NODAL-mediated gene transcription in the left lateral plate mesoderm (LPM). Plays an essential role in differentiation of the adrenal cortex from the adrenogonadal primordium (AGP); stimulates WT1-mediated transcription activation thereby up-regulating the nuclear hormone receptor NR5A1 promoter activity. Associates with chromatin to the PITX2 P1 promoter region. {ECO:0000269|PubMed:11581164, ECO:0000269|PubMed:12586840, ECO:0000269|PubMed:15051727}.;
Disease: DISEASE: Ventricular septal defect 2 (VSD2) [MIM:614431]: A common form of congenital cardiovascular anomaly that may occur alone or in combination with other cardiac malformations. It can affect any portion of the ventricular septum, resulting in abnormal communications between the two lower chambers of the heart. Classification is based on location of the communication, such as perimembranous, inlet, outlet (infundibular), central muscular, marginal muscular, or apical muscular defect. Large defects that go unrepaired may give rise to cardiac enlargement, congestive heart failure, pulmonary hypertension, Eisenmenger's syndrome, delayed fetal brain development, arrhythmias, and even sudden cardiac death. {ECO:0000269|PubMed:16287139}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atrial septal defect 8 (ASD8) [MIM:614433]: A congenital heart malformation characterized by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria. {ECO:0000269|PubMed:16287139}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.372

Intolerance Scores

RVIS EVS: -0.29
RVIS percentile EVS: 32.94

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.924

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium