LMX1A

protein-coding

LIM homeobox transcription factor 1 alpha, the group of LIM class homeoboxes

Gene summary

This gene encodes a homeodomain and LIM-domain containing protein. The encoded protein is a transcription factor that acts as a positive regulator of insulin gene transcription. This gene also plays a role in the development of dopamine producing neurons during embryogenesis. Mutations in this gene are associated with an increased risk of developing Parkinson's disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

Previous symbols:

LMX1

MANE transcript

NM_177398.4

Inheritance

AD, SD, AR

ClinVar variants

P:12U:76B:19

Top phenotype

Deafness, autosomal dominant 7

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr1:165,201,867-165,356,715

External References & Databases

Ensembl (ENSG00000162761)

Transcript & Mutation Effects

hg38 • Region Span ~154.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant nonsyndromic hearing loss 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011074

Submitter: Ambry Genetics

autosomal dominant nonsyndromic hearing loss 7STRONG

Inheritance Pattern: SD

Disease ID:MONDO:0011074

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011074

Submitter: Ambry Genetics

autosomal dominant nonsyndromic hearing loss 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011074

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: ClinGen

LMX1A was first reported in relation to autosomal dominant nonsyndromic deafness in 2018 (Wesdorp et al., PMID: 29754270). In affected probands, the degree of hearing loss ranges from mild to profound, and the age of onset from congenital to middle adulthood. Also, the hearing loss may be symmetrical or asymmetrical. 12 variants (missense, nonsense, frameshift) that have been reported in at least 26 probands in 7 publications (PMIDs: 29754270, 32840933, 35254497, 35711095, 36140227, 36519758, 38056549) are included in this curation. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse models; PMIDs: 10693804, 23226461; https://www.jax.org/strain/002624). Three homozygous mutant mouse models show deafness, inner ear structural anomalies, shortened tails, white belly spotting, and atypical behavior. In summary, there is definitive evidence supporting the relationship between LMX1A and autosomal dominant nonsyndromic deafness. 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 Hearing Loss GCEP on the meeting date 4/16/25 (SOP Version 11).

Moebius syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008006

Submitter: Ambry Genetics

hearing loss, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 7AD

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 29754270

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LMX1A variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 69

not providedTotal: 41

LMX1A-related disorderTotal: 30

Autosomal dominant nonsyndromic hearing loss 7Total: 19

SchizophreniaTotal: 1

Autosomal-Recessive Hereditary Hearing ImpairmentTotal: 1

Sensorineural hearing loss disorderTotal: 1

Monogenic hearing lossTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_177398.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	12 clinvar	1 clinvar	14
missense	3 clinvar	2 clinvar	74 clinvar	6 clinvar		85
nonsense	1 clinvar	4 clinvar	1 clinvar			6
start loss						0
frameshift	1 clinvar	1 clinvar				2
splice donor/acceptor (+/-2bp)						0
Total	5	7	76	18	1	107

Highest pathogenic variant AF is 0.00001177166

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_177398.4	RefSeq	NP_796372.1	8	MANE Select
ENST00000342310.7	Ensembl	ENSP00000340226.3	8	MANE Select
NM_001174069.2	RefSeq	NP_001167540.1	8	Standard
ENST00000294816.6	Ensembl	ENSP00000294816.2	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Dopaminergic Neurogenesis

Biological Process

regulation of cell growth
axon guidance
memory
locomotory behavior
dentate gyrus development

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
protein binding
metal ion binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000342310
Coding exons: 8
Length: 154849
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125731
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.00	175	216	0.808	0.0000114	2500
Missense (PolyPhen)		56	91.757	0.61031		1036
Synonymous	0.565	82	88.8	0.924	0.00000482	725
Loss of Function	4.06	2	23.0	0.0870	0.00000132	232

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a transcriptional activator by binding to an A/T-rich sequence, the FLAT element, in the insulin gene promoter. Required for development of the roof plate and, in turn, for specification of dorsal cell fates in the CNS and developing vertebrae (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.230

Intolerance Scores

LoFtool: 0.0623
RVIS EVS: -0.74
RVIS percentile EVS: 13.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.986

Gene Damage Prediction

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