LHX3

Chr 9AR

LIM homeobox 3

Also known as: CPHD3, LIM3, M2-LHX3

NCBI Gene: 8022ENSG00000107187UniProt: Q9UBR4

This gene encodes a member of a large family of proteins which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor that is required for pituitary development and motor neuron specification. Mutations in this gene cause combined pituitary hormone deficiency 3. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

Primary Disease Associations & Inheritance

Pituitary hormone deficiency, combined, 3MIM #221750
AR
616
ClinVar variants
83
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— LHX3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
83 Pathogenic / Likely Pathogenic· 190 VUS of 616 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.74LOEUF
pLI 0.011
Z-score 2.31
OE 0.38 (0.20–0.74)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.33Z-score
OE missense 0.94 (0.84–1.05)
218 obs / 232.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.38 (0.20–0.74)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.84–1.05)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 6 / 16.0Missense obs/exp: 218 / 232.3Syn Z: 0.09

ClinVar Variant Classifications

616 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic64
Likely Pathogenic19
VUS190
Likely Benign317
Benign18
Conflicting8
64
Pathogenic
19
Likely Pathogenic
190
VUS
317
Likely Benign
18
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
1
53
0
64
Likely Pathogenic
15
2
2
0
19
VUS
2
147
34
7
190
Likely Benign
0
2
85
230
317
Benign
0
0
18
0
18
Conflicting
—8
Total27152192237616

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

View in ClinVar →

Protein Context — Lollipop Plot

LHX3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

LHX3-related pituitary hormone deficiency combined

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Pituitary hormone deficiency, combined, 3

MIM #221750

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — LHX3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pituitary Hypoplasia.
Gangat M et al.·Endocrinol Metab Clin North Am
2017Review
Hearing impairment and vestibular function in patients with a pathogenic splice variant in the LHX3 gene.
Kjellgren Å et al.·BMC Med Genomics
2024Cohort
Hypopituitarism oddities: congenital causes.
Kelberman D et al.·Horm Res
2007Review
Congenital Hypopituitarism: Various Genes, Various Phenotypes.
Xatzipsalti M et al.·Horm Metab Res
2019Review
Genetic disorders of the pituitary.
Cohen LE·Curr Opin Endocrinol Diabetes Obes
2012Review
Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders.
Gregory LC et al.·Genet Med
2023Cohort
Genetic disorders of human growth.
Wajnrajch MP·J Pediatr Endocrinol Metab
2002Review
The molecular basis of hypoprolactinaemia.
Finn BP et al.·Rev Endocr Metab Disord
2024Review
Foetal and neonatal thyroid disorders.
Radetti G et al.·Minerva Pediatr
2002Review
LHX3 is an advanced-stage prognostic biomarker and metastatic oncogene in hepatocellular carcinoma.
Huang B et al.·Cancer Biomark
2019
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools