FOXL1

protein-coding

forkhead box L1, the group of Forkhead boxes

Gene summary

This gene encodes a member of the forkhead/winged helix-box (FOX) family of transcription factors. FOX transcription factors are characterized by a distinct DNA-binding forkhead domain and play critical roles in the regulation of multiple processes including metabolism, cell proliferation and gene expression during ontogenesis. [provided by RefSeq, Nov 2012]

Previous symbols:

FKHL11

MANE transcript

NM_005250.3

Inheritance

ClinVar variants

U:69B:2

Top phenotype

Otosclerosis 11

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr16:86,576,368-86,583,478

External References & Databases

Ensembl (ENSG00000176678)

Transcript & Mutation Effects

hg38 • Region Span ~7.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*FOXL1* was first reported in relation to autosomal dominant congenital heart disease in 2012 (Iascone et al., PMID: 21457232). Five unique variants (missense, duplication, regulatory and gross duplication) in five individuals with hypoplastic left heart syndrome were reported in three publications (PMIDs: 21457232, 28473349, 29368431), but none of them were scored due to high minor allele frequency in gnomAD v.4. No experimental evidence has been reported in the literature supporting this gene-disease relationship. In summary, the evidence supporting the relationship between *FOXL1* and autosomal dominant congenital heart disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *FOXL1* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 11/27/2023 (SOP Version 10)

otosclerosis 11LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0957928

Submitter: Ambry Genetics

otosclerosis 11LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0957928

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Otosclerosis 11AD

Manifestation: Audiologic/Otolaryngologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Stapedectomy has been reported as helpful, but cochlear implant may be necessary

Refs: 34633540

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FOXL1 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 71

not providedTotal: 3

Otosclerosis 11Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005250.3. 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						0
missense			69 clinvar	2 clinvar		71
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	69	2	0	71

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005250.3	RefSeq	NP_005241.1	1	MANE Select
ENST00000320241.5	Ensembl	ENSP00000326272.3	1	MANE Select
ENST00000593625.1	Ensembl	ENSP00000472376.1	1	Standard
ENST00000954000.1	Ensembl	ENSP00000624059.1	1	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
foxl1	Danio rerio	Structure: hyosymplectic cartilage Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

foxl1

Danio rerio

Structure: hyosymplectic cartilage

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ectoderm Differentiation

Biological Process

regulation of transcription by RNA polymerase II
multicellular organism development
visceral mesoderm-endoderm interaction involved in midgut development
heart development
anatomical structure morphogenesis

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity
DNA binding, bending
sequence-specific DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000320241
Coding exons: 1
Length: 5330
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	-0.281	199	188	1.06	0.00000887	2177
Missense (PolyPhen)		60	75.307	0.79674		895
Synonymous	-2.63	119	87.7	1.36	0.00000433	775
Loss of Function	1.23	3	6.34	0.473	2.75e-7	73

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: Transcription factor required for proper proliferation and differentiation in the gastrointestinal epithelium. Target gene of the hedgehog (Hh) signaling pathway via GLI2 AND GLI3 transcription factors (By similarity). {ECO:0000250}.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.333

Gene Damage Prediction

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