LEMD3

Chr 12AD

LEM domain containing 3

Also known as: MAN1

NCBI Gene: 23592ENSG00000174106UniProt: Q9Y2U8

This locus encodes a LEM domain-containing protein. The encoded protein functions to antagonize transforming growth factor-beta signaling at the inner nuclear membrane. Two transcript variants encoding different isoforms have been found for this gene. Mutations in this gene have been associated with osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.[provided by RefSeq, Nov 2009]

Primary Disease Associations & Inheritance

Buschke-Ollendorff syndromeMIM #166700
AD
Osteopoikilosis with or without melorheostosisMIM #166700
AD
539
ClinVar variants
46
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— LEMD3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
46 Pathogenic / Likely Pathogenic· 308 VUS of 539 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.25LOEUF
pLI 0.999
Z-score 5.25
OE 0.12 (0.06–0.25)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
-0.26Z-score
OE missense 1.03 (0.96–1.11)
485 obs / 469.1 exp
Tolerant

Tolerant to missense variation

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.0.12 (0.06–0.25)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.03 (0.96–1.11)
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.1.12
0≤1.21.6
LoF obs/exp: 5 / 41.5Missense obs/exp: 485 / 469.1Syn Z: -1.22

ClinVar Variant Classifications

539 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic8
VUS308
Likely Benign159
Benign15
Conflicting11
38
Pathogenic
8
Likely Pathogenic
308
VUS
159
Likely Benign
15
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
20
0
18
0
38
Likely Pathogenic
4
1
3
0
8
VUS
3
283
20
2
308
Likely Benign
0
5
35
119
159
Benign
0
0
10
5
15
Conflicting
—11
Total2728986126539

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

View in ClinVar →

Protein Context — Lollipop Plot

LEMD3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

LEMD3-related Buschke-Ollendorff syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkinSkeletal
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Buschke-Ollendorff syndrome

MIM #166700

Molecular basis of disorder known

Autosomal dominant

Osteopoikilosis with or without melorheostosis

MIM #166700

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The inner nuclear membrane protein LEMD3 organizes the 3D chromatin architecture to maintain vascular smooth muscle cell identity.
Li W et al.·Nat Commun
2025
Identification of a novel LEMD3 Y871X mutation in a three-generation family with osteopoikilosis and review of the literature.
Zhang Q et al.·J Endocrinol Invest
2016Review
A novel LEMD3 pathogenic variant in a son and mother with osteopoikilosis.
Elmaoğulları S et al.·Turk J Pediatr
2019Case report
Osteopoikilosis and multiple exostoses caused by novel mutations in LEMD3 and EXT1 genes respectively--coincidence within one family.
Baasanjav S et al.·BMC Med Genet
2010
Melorheostosis and Osteopoikilosis: A Review of Clinical Features and Pathogenesis.
Wordsworth P et al.·Calcif Tissue Int
2019Review
Melorheostosis: a Rare Sclerosing Bone Dysplasia.
Kotwal A et al.·Curr Osteoporos Rep
2017Review
Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis.
Zhang Y et al.·Clin Genet
2009Case report
Melorheostosis and Osteopoikilosis Clinical and Molecular Description of an Italian Case Series.
Gnoli M et al.·Calcif Tissue Int
2019Cohort
A novel LEMD3 mutation common to patients with osteopoikilosis with and without melorheostosis.
Couto AR et al.·Calcif Tissue Int
2007Case report
Identification of unique venous thromboembolism-susceptibility variants in African-Americans.
Heit JA et al.·Thromb Haemost
2017
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