ZIC3

Chr XXLR

Zic family zinc finger 3

Also known as: HTX, HTX1, VACTERLX, ZNF203

NCBI Gene: 7547 ENSG00000156925 UniProt: O60481 OMIM: 300265

The protein functions as a transcriptional activator that binds to GLI-consensus sequences and is required for axial midline development and left-right asymmetry specification during early embryogenesis. Loss-of-function mutations cause X-linked visceral heterotaxy with congenital heart defects and left-right axis defects in organs, as well as VACTERL association. The condition follows X-linked recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLRLOEUF 0.363 OMIM phenotypes

Clinical Summary— ZIC3

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Gene-Disease Validity (ClinGen)

congenital heart disease with heterotaxy syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

33 unique Pathogenic / Likely Pathogenic· 93 VUS of 186 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.36LOEUF

pLI 0.925

Z-score 2.67

OE 0.00 (0.00–0.36)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.52Z-score

OE missense 0.49 (0.41–0.58)

94 obs / 192.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.36)

0≤0.351.4

Missense OE?0.49 (0.41–0.58)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 0 / 8.3Missense obs/exp: 94 / 192.2Syn Z: 0.92

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveZIC3-related heterotaxy syndromeLOFXLR

definitiveZIC3-related VACTERL association with or without hydrocephalusOTHERXLR

This gene — mechanism propensity

0.4884th %ile

GOF

0.2198th %ile

LOF

0.90top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 76% of P/LP variants are LoF · LOEUF 0.36 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

186 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22

Likely Pathogenic11

VUS93

Likely Benign34

Benign12

Conflicting10

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	19	1	2	0	22
Likely Pathogenic	6	5	0	0	11
VUS	2	72	17	2	93
Likely Benign	0	8	2	24	34
Benign	0	2	6	4	12
Conflicting	—				10
Total	27	88	27	30	182

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

108 pathogenic / likely-pathogenic (of 114) ClinVar copy-number / structural variants overlap ZIC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →