LMNB1

Chr 5AD

lamin B1

Also known as: ADLD, LMN, LMN2, LMNB, MCPH26

NCBI Gene: 4001 ENSG00000113368 UniProt: P20700 OMIM: 150340

The protein is a B-type lamin that forms part of the nuclear lamina structure. Duplications cause autosomal dominant adult-onset leukodystrophy (ADLD), while other mutations result in autosomal dominant primary microcephaly 26. The pathogenic mechanism involves a dominant-negative effect where mutant protein disrupts normal nuclear envelope function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes one of the two B-type lamin proteins and is a component of the nuclear lamina. A duplication of this gene is associated with autosomal dominant adult-onset leukodystrophy (ADLD). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.411 OMIM phenotype

Clinical Summary— LMNB1

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Gene-Disease Validity (ClinGen)

microcephaly 26, primary, autosomal dominant · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.55) — some intolerance to loss-of-function variants.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 64 VUS of 98 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — LMNB1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.555

Z-score 3.92

OE 0.21 (0.11–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.63Z-score

OE missense 0.74 (0.66–0.82)

229 obs / 309.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.21 (0.11–0.41)

0≤0.351.4

Missense OE?0.74 (0.66–0.82)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 6 / 28.6Missense obs/exp: 229 / 309.5Syn Z: 0.41

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveLMNB1-related developmental disorderOTHERAD

This gene — mechanism propensity

0.83top 10%

GOF

0.7127th %ile

LOF

0.3453th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median · ClinGen TS: Sufficient evidence for dosage pathogenicity

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNDominant negative mutant lamin B proteins that disrupt lamin B assembly in interphase nuclei also disrupted spindle assembly in mitosis.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 16543417 ↗

ClinVar Variant Classifications

98 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS64

Likely Benign16

Conflicting1

Pathogenic

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	6	57	1	0	64
Likely Benign	0	4	3	9	16
Benign	0	0	0	0	0
Conflicting	—				1
Total	6	62	4	9	82

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

View in ClinVar →

1 pathogenic / likely-pathogenic (of 2) ClinVar copy-number / structural variants overlap LMNB1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →