GeneBe

ZIC3

protein-coding

Zic family member 3, the group of Zinc fingers C2H2-type

Gene summary

This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. This nuclear protein probably functions as a transcription factor in early stages of left-right body axis formation. Mutations in this gene cause X-linked visceral heterotaxy, which includes congenital heart disease and left-right axis defects in organs. [provided by RefSeq, Jul 2008]

Previous symbols:
  • HTX1

MANE transcript

NM_003413.4

Inheritance

XL

ClinVar variants

P:45U:82B:47

Top phenotype

Congenital heart defects, nonsyndromic, 1, X-linked; Heterotaxy, visceral, 1, X-linked; VACTERL association, X-linked, with or without hydrocephalus

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:137,566,127-137,577,691

External References & Databases

Ensembl (ENSG00000156925)NCBI Gene (7547)OMIM (300265)HGNC:12874GenCCUniProt (O60481)AlphaFoldClinVar (ZIC3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~11.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

VACTERL association, X-linked, with or without hydrocephalusSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010752

Submitter: Genomics England PanelApp

VACTERL association, X-linked, with or without hydrocephalusDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010752

Submitter: G2P

VACTERL association, X-linked, with or without hydrocephalusMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010752

Submitter: Ambry Genetics

heterotaxy, visceral, 1, X-linkedMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010607

Submitter: Ambry Genetics

heterotaxy, visceral, 1, X-linkedDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010607

Submitter: G2P

VACTERL association, X-linked, with or without hydrocephalusSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010752

Submitter: PanelApp Australia

heterotaxy, visceral, 1, X-linkedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010607

Submitter: PanelApp Australia

congenital heart disease with heterotaxy syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:1060197

Submitter: ClinGen

*ZIC3* was first reported in relation to X-linked recessive congenital heart disease with heterotaxy in 2004 (Ware et al., PMID: 14681828). In addition to congenital heart disease, this condition is associated with situs ambiguus (such as impacting the spleen, lungs, and liver). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in inheritance pattern or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: Congenital heart defects, nonsyndromic, multiple types, 1, X-linked (OMIM: 306955); Heterotaxy, visceral, 1, X-linked (OMIM: 306955); and VACTERL association, X-linked (OMIM: 314390). Fourteen variants (missense, small in-frame insertions, nonsense, frameshift) that have been reported in at least 14 probands in 5 publications (PMIDs: 14681828, 23427188, 24123890, 30622330, 36567274) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (2 mouse models; PMIDs: 11959836, 16496285, 23999067). Null mutant mice show embryonic lethality, complex congenital heart disease, and heterotaxy. Hypomorphic mutant mice show complex congenital heart disease, heterotaxy, and minimal embryonic lethality. In summary, there is definitive evidence supporting the relationship between *ZIC3* and X-linked recessive congenital heart disease with heterotaxy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 10/7/2025 (SOP Version 11).

heterotaxy, visceral, 1, X-linkedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010607

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Congenital heart defects, nonsyndromic, 1, X-linked; Heterotaxy, visceral, 1, X-linked; VACTERL association, X-linked, with or without hydrocephalusXL

Manifestation: Cardiovascular; Genitourinary; Gastrointestinal; Musculoskeletal; Neurologic; Pulmonary; Renal

Intervention: Cardiovascular

Rationale: The conditions can include congenital cardiac anomalies, and awareness may allow early identification and management

Refs: 3674105; 9354794; 10980576; 14681828; 17295247; 20452998; 21465648; 21864452; 23427188; 24123890Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZIC3 variants in ClinVar

7 Conditions Cataloged
Heterotaxy, visceral, 1, X-linkedTotal: 102
not providedTotal: 43
Inborn genetic diseasesTotal: 37
ZIC3-related disorderTotal: 28
not specifiedTotal: 18
VACTERL association, X-linked, with or without hydrocephalusTotal: 15
Congenital heart defects, multiple types, 1, X-linkedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003413.4. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
33
clinvar
1
clinvar
 37
missense
5
clinvar
5
clinvar
76
clinvar
12
clinvar
1
clinvar
 99
nonsense
11
clinvar
5
clinvar
 16
start loss
1
clinvar
 1
frameshift
12
clinvar
5
clinvar
2
clinvar
 19
splice donor/acceptor (+/-2bp)
2
clinvar
 2
Total281782452174

Highest pathogenic variant AF is 0.000015660755

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003413.4RefSeqNP_003404.13MANE Select
ENST00000287538.10EnsemblENSP00000287538.53MANE Select
NM_001330661.1RefSeqNP_001317590.13Standard
ENST00000370606.3EnsemblENSP00000359638.33Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
zic3Danio rerio

Structure: trunk

Quality: increased curvature

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
  • Mesodermal Commitment Pathway
  • POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation
  • Developmental Biology
  • POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation

Biological Process

  • heart looping
  • determination of left/right symmetry
  • central nervous system development
  • anterior/posterior pattern specification
  • cell differentiation

Molecular Function

  • RNA polymerase II regulatory region sequence-specific DNA binding
  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA-binding transcription activator activity, RNA polymerase II-specific
  • DNA-binding transcription factor activity

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000287538
Coding exons
3
Length
11550
Individuals with no LoFs
125744
Homozygous LoFs
1
Heterozygous LoFs
1
Defined
125746
p
0.00000795
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.52941920.4890.00001283068
Missense (PolyPhen)2571.6190.349071104
Synonymous0.9177282.60.8720.00000578937
Loss of Function2.6708.280.005.28e-7147

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000370.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000120.0000088rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Acts as transcriptional activator. Required in the earliest stages in both axial midline development and left-right (LR) asymmetry specification. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'. {ECO:0000269|PubMed:17764085}.;
Disease
DISEASE: Heterotaxy, visceral, 1, X-linked (HTX1) [MIM:306955]: A form of visceral heterotaxy, a complex disorder due to disruption of the normal left-right asymmetry of the thoracoabdominal organs. Visceral heterotaxy or situs ambiguus results in randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another. It can been associated with variety of congenital defects including cardiac malformations. {ECO:0000269|PubMed:14681828, ECO:0000269|PubMed:17295247, ECO:0000269|PubMed:17764085, ECO:0000269|PubMed:18716025, ECO:0000269|PubMed:24123890, ECO:0000269|PubMed:9354794}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: VACTERL association X-linked with or without hydrocephalus (VACTERLX) [MIM:314390]: A syndrome characterized by a non-random association of congenital defects. Affected individuals manifest vertebral anomalies (V), anal atresia (A), cardiac malformations (C), tracheoesophageal fistula (TE), renal anomalies (R) such as urethral atresia with hydronephrosis, and limb anomalies (L) such as hexadactyly, humeral hypoplasia, radial aplasia, and proximally placed thumb. Some patients may have hydrocephalus. Some cases of VACTERL-H are associated with increased chromosome breakage and rearrangement. {ECO:0000269|PubMed:20452998, ECO:0000269|PubMed:24123890}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Congenital heart defects, multiple types, 1, X-linked (CHTD1) [MIM:306955]: A disorder characterized by congenital developmental abnormalities involving structures of the heart. Common defects include transposition of the great arteries, aortic stenosis, atrial septal defect, ventricular septal defect, pulmonic stenosis, and patent ductus arteriosus. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. Some patients with CHTD also have cardiac arrhythmias, which may be due to the anatomic defect itself or to surgical interventions. {ECO:0000269|PubMed:14681828, ECO:0000269|PubMed:17764085, ECO:0000269|PubMed:24123890}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.168

Intolerance Scores

RVIS EVS
0.61
RVIS percentile EVS
83.07

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.539

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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