LMNB1

protein-coding

lamin B1, the group of Lamins

Gene summary

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]

MANE transcript

NM_005573.4

Inheritance

ClinVar variants

P:8U:186B:78

Top phenotype

Leukodystrophy, demyelinating, adult-onset, autosomal dominant; Leukodystrophy, demyelinating, adult-onset, autosomal dominant, atypical

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr5:126,776,623-126,837,020

External References & Databases

Ensembl (ENSG00000113368)

Transcript & Mutation Effects

hg38 • Region Span ~60.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

adult-onset autosomal dominant demyelinating leukodystrophySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008215

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant primary microcephalySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007988

Submitter: Orphanet

adult-onset autosomal dominant demyelinating leukodystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008215

Submitter: Orphanet

microcephaly 26, primary, autosomal dominantDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030928

Submitter: ClinGen

LMNB1 was first associated with primary autosomal dominant microcephaly 26 in 2020 (MCPH26: OMIM #150340) (PMID: 32910914). MCPH26 is characterized by congenital or early-onset progressive microcephaly with global developmental delay and intellectual disability. Affected individuals often present with hypotonia, motor delay, speech impairment, and variable behavioral abnormalities. Additional features may include seizures, feeding difficulties, and growth restriction. Prior to this disease description, LMNB1 was associated with disease in 2006 in autosomal dominant leukodystrophy with autonomic disease (ADLD), which is caused primarily by genomic duplications of a region within chromosome 5q23.2 that includes the entire LMNB1 gene (Padiath et al., PMID: 16951681). ADLD is an adult onset leukodystrophy characterized by progressive motor and cognitive impairment with autonomic symptoms. The LMNB1 gene encodes lamin B1, a major structural component of the nuclear lamina that maintains nuclear shape and integrity, regulates chromatin organization, and supports essential cellular processes including transcription, DNA replication, and nuclear assembly. Heterozygous variants in LMNB1 act in a dominant-negative manner to disrupt lamin B1 function and nuclear lamina stability, leading to abnormal nuclear morphology and altered chromatin organization during brain development. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we identified significant differences in phenotype and molecular mechanism between ADLD and MCPH26 (PMID: 32910914). Therefore, MCPH26 is curated as a distinct disease entity from ADLD. ADLD has been curated by the ClinGen Dosage Sensitivity Working Group. This curation of autosomal dominant MCHP26 included six missense variants and two in-frame deletions reported in 13 probands across three publications (PMIDs: 32910914, 33033404, 33584783). In total we found 8.7 points for genetic evidence. This gene–disease relationship is further supported by 4 points of experimental evidence, including two unique mouse models demonstrating the essential role of lamin B1 in brain development and nuclear structure (PMIDs: 21976703, 15232008). In summary, there is definitive evidence supporting the relationship between LMNB1 and autosomal dominant microcephaly 26, also known as LMNB1-related microcephaly, with rigorous and reproducible evidence in research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date: December 10, 2025 SOP Version #11.

adult-onset autosomal dominant demyelinating leukodystrophyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008215

Submitter: Ambry Genetics

microcephalySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0001149

Submitter: Franklin by Genoox

Examining a cohort of patients with extreme microcephaly, from the Deciphering Developmental Disorders Study, revealed three recurrent LMNB1 variants in seven individuals. In most of the cases those variants were found to be de novo. In additional study, In seven individuals with pronounced primary microcephaly DNA enalysis identified de novo mutations in LMNB1 gene.

microcephaly 26, primary, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030928

Submitter: Labcorp Genetics (formerly Invitae)

leukodystrophy, demyelinating, adult-onset, autosomal dominant, atypicalSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700286

Submitter: PanelApp Australia

leukodystrophy, demyelinating, adult-onset, autosomal dominant, typicalSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700295

Submitter: PanelApp Australia

microcephaly 26, primary, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030928

Submitter: PanelApp Australia

microcephaly 26, primary, autosomal dominantDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030928

Submitter: G2P

Clinical Genomic Database (CGD)

Leukodystrophy, demyelinating, adult-onset, autosomal dominant; Leukodystrophy, demyelinating, adult-onset, autosomal dominant, atypicalAD

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 16951681; 19151023; 21225301; 21909802; 23243074; 23649844; 32910914; 33033404

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LMNB1 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 196

Inborn genetic diseasesTotal: 84

not specifiedTotal: 45

Adult-onset autosomal dominant demyelinating leukodystrophyTotal: 28

Microcephaly 26, primary, autosomal dominantTotal: 21

LMNB1-related disorderTotal: 14

Syndrome with microcephaly as major featureTotal: 5

Leukodystrophy, demyelinating, adult-onset, autosomal dominant, typicalTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005573.4. 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			4 clinvar	47 clinvar	4 clinvar	55
missense	3 clinvar	2 clinvar	167 clinvar	25 clinvar	1 clinvar	198
nonsense			4 clinvar			4
start loss			1 clinvar			1
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar	5 clinvar	1 clinvar		9
Total	5	3	186	73	5	272

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005573.4	RefSeq	NP_005564.1	11	MANE Select
ENST00000261366.10	Ensembl	ENSP00000261366.5	11	MANE Select
NM_001198557.2	RefSeq	NP_001185486.1	9	Standard
ENST00000395354.1	Ensembl	ENSP00000378761.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Apoptosis - Homo sapiens (human)
Fas Ligand (FasL) pathway and Stress induction of Heat Shock Proteins (HSP) regulation
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer,s disease models
Neurodegenerative Diseases

Biological Process

interleukin-12-mediated signaling pathway

Molecular Function

structural molecule activity
protein binding
phospholipase binding
sequence-specific double-stranded DNA binding

Cellular Component

nucleus
nuclear envelope
nuclear inner membrane
lamin filament
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261366
Coding exons: 11
Length: 60398
Individuals with no LoFs: 125735
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125745
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.63	229	310	0.740	0.0000166	3811
Missense (PolyPhen)		40	72.957	0.54826		1019
Synonymous	0.414	108	114	0.951	0.00000595	1114
Loss of Function	3.92	6	28.6	0.210	0.00000136	371

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Lamins are components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane, which is thought to provide a framework for the nuclear envelope and may also interact with chromatin.;
Disease: DISEASE: Leukodystrophy, demyelinating, autosomal dominant, adult- onset (ADLD) [MIM:169500]: A slowly progressive and fatal demyelinating leukodystrophy, presenting in the fourth or fifth decade of life. Clinically characterized by early autonomic abnormalities, pyramidal and cerebellar dysfunction, and symmetric demyelination of the CNS. It differs from multiple sclerosis and other demyelinating disorders in that neuropathology shows preservation of oligodendroglia in the presence of subtotal demyelination and lack of astrogliosis. {ECO:0000269|PubMed:16951681}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.521

Intolerance Scores

LoFtool: 0.181
RVIS EVS: -0.4
RVIS percentile EVS: 26.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.889

Gene Damage Prediction

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