LEFTY2

protein-coding

left-right determination factor 2, the group of Transforming growth factor beta superfamily

Gene summary

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate the mature protein, which plays a role in left-right asymmetry determination of organ systems during development. The protein may also play a role in endometrial bleeding. Mutations in this gene have been associated with left-right axis malformations, particularly in the heart and lungs. Some types of infertility have been associated with dysregulated expression of this gene in the endometrium. This gene is closely linked to both a related family member and a related pseudogene. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

Previous symbols:

TGFB4
EBAF

MANE transcript

NM_003240.5

Inheritance

ClinVar variants

P:1U:98B:74

Top phenotype

Left-right axis malformations

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr1:225,936,598-225,941,383

External References & Databases

Ensembl (ENSG00000143768)

Transcript & Mutation Effects

hg38 • Region Span ~4.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: PanelApp Australia

visceral heterotaxyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018677

Submitter: G2P

congenital heart diseaseNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*LEFTY2* was first reported in relation to autosomal dominant congenital heart disease in 1999 (Kosaki et al., PMID: 10053005). Three variants (a missense, a nonsense, and a chromosomal segment deletion) that have been reported in three probands in two publications (PMIDs: 10053005, 25516202) are included in this curation. However, none were scored. The missense and nonsense mutations are too frequent in the general population, and the chromosomal segment deletion included other CHD-associated genes. The only experimental evidence, a mouse model, was not scored due to the lack of scorable genetic evidence and only a low portion of mice exhibiting cardiac anomalies (PMID: 11703930). In summary, the evidence supporting the relationship between *LEFTY2* 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 *LEFTY2* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 2/6/2022 (SOP Version 10).

Clinical Genomic Database (CGD)

Left-right axis malformationsAD

Manifestation: Cardiovascular; Pulmonary

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Comments: The contributions of variants to clinical disease are unclear

Refs: 10053005

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LEFTY2 variants in ClinVar

5 Conditions Cataloged

Left-right axis malformationsTotal: 132

not specifiedTotal: 80

not providedTotal: 14

LEFTY2-related disorderTotal: 13

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003240.5. 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			3 clinvar	54 clinvar	5 clinvar	62
missense		1 clinvar	88 clinvar	14 clinvar	1 clinvar	104
nonsense			4 clinvar			4
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	1	98	68	6	173

Highest pathogenic variant AF is 0.00003407856

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_003240.5	RefSeq	NP_003231.2	4	MANE Select
ENST00000366820.10	Ensembl	ENSP00000355785.5	4	MANE Select
NM_001172425.3	RefSeq	NP_001165896.1	5	Standard
ENST00000420304.6	Ensembl	ENSP00000388009.2	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lft2	Danio rerio	Structure: endodermal cell Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

lft2

Danio rerio

Structure: endodermal cell

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TGF-beta signaling pathway - Homo sapiens (human)
Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
Cell Differentiation - Index expanded
Cell Differentiation - Index
Mesodermal Commitment Pathway

Biological Process

platelet degranulation
transforming growth factor beta receptor signaling pathway
multicellular organism development
regulation of signaling receptor activity
positive regulation of pathway-restricted SMAD protein phosphorylation

Molecular Function

cytokine activity
transforming growth factor beta receptor binding
growth factor activity

Cellular Component

extracellular region
extracellular space
platelet alpha granule lumen
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366820
Coding exons: 4
Length: 4892
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125717
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.579	214	239	0.895	0.0000157	2302
Missense (PolyPhen)		43	65.797	0.65353		702
Synonymous	-0.210	125	122	1.02	0.00000918	793
Loss of Function	1.72	8	15.2	0.525	8.29e-7	132

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.00011	0.000098	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for left-right (L-R) asymmetry determination of organ systems in mammals. May play a role in endometrial bleeding.;
Disease: DISEASE: Left-right axis malformations (LRAM) [MIM:601877]: The defect includes left pulmonary isomerism, with cardiac anomalies characterized by complete atrioventricular canal defect and hypoplastic left ventricle, and interrupted inferior vena cava. {ECO:0000269|PubMed:10053005}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.527

Intolerance Scores

LoFtool: 0.266
RVIS EVS: 0.33
RVIS percentile EVS: 73.27

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.307

Gene Damage Prediction

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