LBR

protein-coding

lamin B receptor, the group of Tudor domain containing

Gene summary

The protein encoded by this gene belongs to the ERG4/ERG24 family. It localized in the nuclear envelope inner membrane and anchors the lamina and the heterochromatin to the membrane. It may mediate interaction between chromatin and lamin B. Mutations of this gene has been associated with autosomal recessive HEM/Greenberg skeletal dysplasia. Alternative splicing occurs at this locus and two transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002296.4

Inheritance

AR, AD

ClinVar variants

P:37U:223B:102

Top phenotype

Reynolds syndrome; Pelger-Huet anomaly; Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly; Greenberg dysplasia

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr1:225,401,502-225,428,925

External References & Databases

Ensembl (ENSG00000143815)

Transcript & Mutation Effects

hg38 • Region Span ~27.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Greenberg dysplasiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008974

Submitter: G2P

regressive spondylometaphyseal dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018663

Submitter: Orphanet

Greenberg dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008974

Submitter: Orphanet

Greenberg dysplasiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008974

Submitter: Ambry Genetics

regressive spondylometaphyseal dysplasiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0018663

Submitter: ClinGen

LBR was first reported in relation to AR Regressive Spondylometaphyseal Dysplasia in 2013 (Borovik et al., PMID: 23824842). Regressive Spondylometaphyseal Dysplasia, AKA Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, is a rare, primary bone dysplasia characterized by mild short stature, rhizomelic shortening of the arms and legs, bowing of long bones with widened and irregular metaphyses, thoracolumbar kyphosis, and metacarpal shortening. A marked improvement of the radiologic skeletal features is typical. Variants in LBR have been reported in individuals with the following disease entities: Reynold’s syndrome, Greenberg Skeletal Dysplasia, Pelger-Huet anomaly, and Regressive Spondylometaphyseal Dysplasia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism and phenotypic variability. Therefore, the following disease entities have been split into four disease entities, Reynold’s syndrome (OMIM:613471), Greenberg Skeletal Dysplasia (OMIM:215140), Pelger-Huet anomaly (OMIM:169400), and Regressive Spondylometaphyseal Dysplasia (OMIM:618019). The split curation for AR Greenberg Skeletal Dysplasia will be curated separately by the Skeletal Disorders GCEP. Eight missense variants and three nonsense variants that have been reported in eight probands in six publications (PMIDs: 23824842, 25348816, 29068549, 30448303, 34467646, 36400164) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by a mouse model (PMID: 12490533). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date August 7th, 2023 (SOP Version 9).

Greenberg dysplasiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008974

Submitter: ClinGen

LBR was first reported in relation to AR Greenberg Skeletal Dysplasia in 2003 (Waterham et al., PMID: 12618959). Greenberg Skeletal Dysplasia is a prenatally lethal chondrodystrophy, characterized by fetal hydrops, short limbs, and abnormal chondro-osseous calcification. Variants in LBR have been reported in individuals with the following disease entities: Reynold’s syndrome, Greenberg Skeletal Dysplasia, Pelger-Huet anomaly, and Regressive Spondylometaphyseal Dysplasia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism and phenotypic variability. Therefore, the following disease entities have been split into four disease entities, Reynold’s syndrome (OMIM:613471), Greenberg Skeletal Dysplasia (OMIM:215140), Pelger-Huet anomaly (OMIM:169400), and Regressive Spondylometaphyseal Dysplasia (OMIM:618019). The split curation for AR Regressive Spondylometaphyseal Dysplasia has been curated separately by the Skeletal Disorders GCEP. Three missense variants, three frameshift, and one indel variants that have been reported in six probands in five publications (PMIDs: 12618959, 18382993, 21327084, 30518689, 30561119) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by expression evidence (PMID: 21327084). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date November 1st, 2023 (SOP Version 9).

regressive spondylometaphyseal dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018663

Submitter: Labcorp Genetics (formerly Invitae)

Greenberg dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008974

Submitter: Labcorp Genetics (formerly Invitae)

Pelger-Huet anomalyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008214

Submitter: Ambry Genetics

Greenberg dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008974

Submitter: PanelApp Australia

Pelger-Huet anomalySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008214

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Reynolds syndrome; Pelger-Huet anomaly; Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly; Greenberg dysplasiaAD/AR

Manifestation: Craniofacial; Hematologic; Musculoskeletal

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: 5553949; 3475111; 12118250; 14684694; 12618959; 20522425; 22338047

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LBR variants in ClinVar

20 Conditions Cataloged

not providedTotal: 334

Inborn genetic diseasesTotal: 95

Greenberg dysplasiaTotal: 78

LBR-related disorderTotal: 40

not specifiedTotal: 38

Pelger-Huët anomalyTotal: 22

Regressive spondylometaphyseal dysplasiaTotal: 17

Connective tissue disorderTotal: 15

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002296.4. 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			2 clinvar	75 clinvar		77
missense	4 clinvar	11 clinvar	215 clinvar	26 clinvar	1 clinvar	257
nonsense	5 clinvar	2 clinvar	1 clinvar			8
start loss	1 clinvar					1
frameshift	6 clinvar	3 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	4 clinvar			9
Total	18	19	223	101	1	362

Highest pathogenic variant AF is 0.00003779355

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 64 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002296.4	RefSeq	NP_002287.2	13	MANE Select
ENST00000272163.9	Ensembl	ENSP00000272163.4	13	MANE Select
NM_194442.3	RefSeq	NP_919424.1	13	Standard
ENST00000338179.6	Ensembl	ENSP00000339883.2	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gastric Cancer Network 2
ATM Signaling Network in Development and Disease
Metabolism of lipids
zymosterol biosynthesis
Metabolism

Biological Process

cholesterol biosynthetic process
sterol biosynthetic process
oxidation-reduction process

Molecular Function

DNA binding
RNA binding
protein binding
lamin binding
delta14-sterol reductase activity

Cellular Component

nuclear envelope
nuclear inner membrane
integral component of nuclear inner membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000338179
Coding exons: 13
Length: 27424
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125748
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.289	337	352	0.957	0.0000206	4000
Missense (PolyPhen)		136	156.68	0.86803		1785
Synonymous	1.19	110	127	0.866	0.00000725	1189
Loss of Function	4.29	9	37.2	0.242	0.00000249	387

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Anchors the lamina and the heterochromatin to the inner nuclear membrane. {ECO:0000269|PubMed:10828963}.;
Disease: DISEASE: Pelger-Huet anomaly (PHA) [MIM:169400]: An autosomal dominant inherited abnormality of granulocytes, characterized by abnormal ovoid shape, reduced nuclear segmentation and an apparently looser chromatin structure. {ECO:0000269|PubMed:14617022}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Greenberg dysplasia (GRBGD) [MIM:215140]: A rare autosomal recessive chondrodystrophy characterized by early in utero lethality. Affected fetuses typically present with fetal hydrops, short-limbed dwarfism, and a marked disorganization of chondro-osseous calcification, and ectopic ossification centers. {ECO:0000269|PubMed:12618959}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Reynolds syndrome (REYNS) [MIM:613471]: A syndrome specifically associating limited cutaneous systemic sclerosis and primary biliary cirrhosis. It is characterized by liver disease, telangiectasia, abrupt onset of digital paleness or cyanosis in response to cold exposure or stress (Raynaud phenomenon), and variable features of scleroderma. The liver disease is characterized by pruritis, jaundice, hepatomegaly, increased serum alkaline phosphatase and positive serum mitochondrial autoantibodies, all consistent with primary biliary cirrhosis. {ECO:0000269|PubMed:20522425}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.291

Intolerance Scores

LoFtool: 0.0224
RVIS EVS: -0.71
RVIS percentile EVS: 14.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.581

Gene Damage Prediction

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