LEMD2

Chr 6ARAD

LEM domain nuclear envelope protein 2

Also known as: CTRCT42, LEM2, MARUPS, NET25, dJ482C21.1

NCBI Gene: 221496ENSG00000161904UniProt: Q8NC56

This gene encodes a LEM domain-containing transmembrane protein of the inner nuclear membrane. The protein is involved in nuclear structure organization and plays a role in cell signaling and differentiation. Mutations in this gene result in Cataract 46, juvenile-onset. Multiple transcript variants have been found for this gene. [provided by RefSeq, Feb 2017]

Primary Disease Associations & Inheritance

Cataract 46, juvenile-onsetMIM #212500
AR
Marbach-Rustad progeroid syndromeMIM #619322
AD
133
ClinVar variants
7
Pathogenic / LP
0.75
pLI score
0
Active trials
Clinical Summary— LEMD2
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.75) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
7 Pathogenic / Likely Pathogenic· 81 VUS of 133 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.41LOEUF
pLI 0.753
Z-score 3.58
OE 0.18 (0.09–0.41)
Moderately constrained

More LoF-intolerant than ~75% 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.
1.82Z-score
OE missense 0.67 (0.58–0.76)
157 obs / 235.4 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.0.18 (0.09–0.41)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.58–0.76)
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.0.90
0≤1.21.6
LoF obs/exp: 4 / 22.2Missense obs/exp: 157 / 235.4Syn Z: 0.81

ClinVar Variant Classifications

133 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6
Likely Pathogenic1
VUS81
Likely Benign17
Benign25
Conflicting3
6
Pathogenic
1
Likely Pathogenic
81
VUS
17
Likely Benign
25
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
4
0
6
Likely Pathogenic
0
0
1
0
1
VUS
0
78
3
0
81
Likely Benign
0
1
6
10
17
Benign
0
2
19
4
25
Conflicting
—3
Total1823314133

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

View in ClinVar →

Protein Context — Lollipop Plot

LEMD2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

LEMD2-related early progeroid syndrome

moderate
ADUndeterminedAltered Gene Product Structure
Dev. DisordersSkin
G2P ↗
missense variant

LEMD2-related cataract, juvenile-onset

strong
ARUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cataract 46, juvenile-onset

MIM #212500

Molecular basis of disorder known

Autosomal recessive

Marbach-Rustad progeroid syndrome

MIM #619322

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — LEMD2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mechanistic Insights of the LEMD2 p.L13R Mutation and Its Role in Cardiomyopathy.
Chen R et al.·Circ Res
2023
LEMD2-associated progeroid syndrome: Expanding the phenotype of the nuclear envelopathy caused by a defect in LEMD2 gene.
Matter A et al.·Aging Cell
2024Case report
The third case of Marbach-Rustad progeroid syndrome caused by a de novo LEMD2 variant.
Lu Z et al.·Clin Genet
2024
Pathogenic genetic variants identified in Australian families with paediatric cataract.
Jones JL et al.·BMJ Open Ophthalmol
2022
The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping.
Marbach F et al.·Am J Hum Genet
2019
BAF facilitates interphase nuclear membrane repair through recruitment of nuclear transmembrane proteins.
Young AM et al.·Mol Biol Cell
2020
A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.
Ried JS et al.·Nat Commun
2016
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