FOXH1

protein-coding

forkhead box H1, the group of Forkhead boxes

Gene summary

FOXH1 encodes a human homolog of Xenopus forkhead activin signal transducer-1. FOXH1 protein binds SMAD2 and activates an activin response element via binding the DNA motif TGT(G/T)(T/G)ATT. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003923.3

Inheritance

ClinVar variants

P:7U:171B:69

Top phenotype

Congenital heart malformations

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr8:144,473,412-144,475,849

External References & Databases

Ensembl (ENSG00000160973)

Transcript & Mutation Effects

hg38 • Region Span ~2.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: PanelApp Australia

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*FOXH1* was first reported in relation to autosomal dominant congenital heart disease (CHD) in 2010 (De Luca et al., PMID: 19933292). *FOXH1* has also been implicated in holoprosencephaly, however, the relationship between *FOXH1* and congenital heart disease was evaluated separately from holoprosencephaly due to differences in clinical presentation. At least seven unique missense variants were reported in ten individuals with CHD (PMID: 32003456). Experimental evidence supporting this gene disease relationship included expression in the outflow tract, common atrium, and ventricle of human embryos, protein interaction data with MEF2C and NKX2-5, a zebrafish rescue model which demonstrated dosage-dependent differences in rescue potential, and a mouse null model that failed to form the outflow tract and right ventricle (PMIDs: 15363409, 18538293, 32003456). In summary, there is limited evidence supporting the relationship between *FOXH1* and autosomal dominant congenital heart disease. Although more human genetic evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date December 3rd, 2024 (SOP Version 11).

congenital heart malformationLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0019512

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)

Congenital heart malformationsAD

Manifestation: Cardiovascular; Craniofacial; Endocrine; Neurologic

Intervention: Cardiovascular

Rationale: The condition may involve congenital heart anomalies, which may benefit from early identification and management

Comments: Individuals with holoprosencephaly may demonstrate endocrine anomalies, including diabetes insipidus

Refs: 18538293

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FOXH1 variants in ClinVar

6 Conditions Cataloged

Holoprosencephaly sequenceTotal: 140

not providedTotal: 72

Inborn genetic diseasesTotal: 72

not specifiedTotal: 27

FOXH1-related disorderTotal: 15

Conotruncal defectTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003923.3. 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			2 clinvar	51 clinvar	4 clinvar	57
missense		7 clinvar	161 clinvar	13 clinvar	1 clinvar	182
nonsense			2 clinvar			2
start loss			2 clinvar			2
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	7	171	64	5	247

Highest pathogenic variant AF is 0.00000309913

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003923.3	RefSeq	NP_003914.1	3	MANE Select
ENST00000377317.5	Ensembl	ENSP00000366534.4	3	MANE Select
ENST00000935086.1	Ensembl	ENSP00000605145.1	3	Standard
ENST00000935086.2	Ensembl	ENSP00000605145.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
foxh1	Danio rerio	Structure: secondary motor neuron Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

foxh1

Danio rerio

Structure: secondary motor neuron

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TGF-Ncore
Heart Development
Endoderm Differentiation
Mesodermal Commitment Pathway
TGF-beta Signaling Pathway

Biological Process

negative regulation of transcription by RNA polymerase II
heart looping
secondary heart field specification
outflow tract morphogenesis
cardiac right ventricle morphogenesis

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity
protein binding

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
transcription factor complex
activin responsive factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377317
Coding exons: 3
Length: 2924
Individuals with no LoFs: 125497
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125514
p: 0.0000677

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-2.55	278	182	1.53	0.00000877	2255
Missense (PolyPhen)		74	63.612	1.1633		858
Synonymous	-2.59	110	80.5	1.37	0.00000408	810
Loss of Function	1.93	4	10.9	0.368	4.76e-7	127

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000086	0.000079	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional activator. Recognizes and binds to the DNA sequence 5'-TGT[GT][GT]ATT-3'. Required for induction of the goosecoid (GSC) promoter by TGF-beta or activin signaling. Forms a transcriptionally active complex containing FOXH1/SMAD2/SMAD4 on a site on the GSC promoter called TARE (TGF-beta/activin response element). {ECO:0000269|PubMed:9702198}.;

Recessive Scores

pRec: 0.242

Intolerance Scores

LoFtool: 0.137
RVIS EVS: 0
RVIS percentile EVS: 53.85

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.904

Gene Damage Prediction

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