LMNA
protein-codinglamin A/C, the group of Lamins
Gene summary
The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]
- LMN1
- CMD1A
- LGMD1B
- PRO1
- LMNL1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~57.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008310
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011569
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012417
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0030781
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014676
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011569
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007906
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0016587
Submitter: ClinGen
The first publication that associated LMNA variants with ARVC was published in 2012 and reported four patients without desmosomal variants that carried LMNA variants (22199124). These patients met 2010 TCC for ARVC and two had microscopic tissue evaluation confirming interstitial fibrosis and fatty replacement suggesting ARVC phenotype. One variant, p. Arg644Cys under 2015 ACMG criteria no longer is classified as a pathogenic variant. This study also included experimental evidence as immunohistochemistry staining of the biopsies did show delocalization of plakoglobin, which has been reported as pathologic for ARVC phenotype. Another study (25837155) in 2015 showed segregation in a large Italian family; however only the proband met ARVC TFC, the remaining 7 affected individuals only met borderline criteria for ARVC. Another study in 2016 (26620845) identified two LMNA variants in two probands. One only met borderline ARVC criteria with severe RV involvement and frequent PVCs. Experimental evidence was included as RV endomyocardial biopsy did demonstrate fibrous tissue replacement of the myocardium. LMNA mutations associated with ARVC appear to be very rare and the observed phenotypes frequently overlap with dilated cardiomyopathy with conduction system abnormalities and atrial arrhythmias.
Inheritance Pattern: AD
Disease ID:MONDO:0021569
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012417
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008310
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007906
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0030781
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011569
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007906
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007269
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0004981
Submitter: Ambry Genetics
Inheritance Pattern: SD
Disease ID:MONDO:0021569
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011569
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0016587
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0000465
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0008915
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0010143
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015470
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0021569
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0008310
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012417
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009557
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0020336
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019321
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008310
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007906
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009557
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008406
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011569
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018203
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007269
Submitter: Orphanet
Inheritance Pattern: SD
Disease ID:MONDO:0017230
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012417
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007269
Submitter: ClinGen
LMNA was originally evaluated for DCM by ClinGen DCM GCEP on October 2, 2020. Evidence of the association of this gene with DCM was re-evaluated on 4/13/2025. As a result, the classification did not change. A summary of the information contributing to the classification of the gene at the time of re-evaluation is summarized herein. LMNA was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 1999 (Fatkin et al, 1999, PMID 10580070). The LMNA gene, encoding the highly conserved lamin A and C proteins, is a highly conserved gene that undergoes alternative splicing giving rise to prelamin A and lamin C, which can be found expressed in a wide range of tissues, including heart and skeletal muscles. Human genetic evidence supporting this gene-disease relationship includes case-level data, segregation data, and case-control data. Many variants have been reported in this gene of missense and predicted null consequences in humans with isolated DCM, over more than 20 years (Fatkin et al, 1999, PMID 10580070; Jakobs et al, 2001, PMID 11561226; Hershberger et al, 2002, PMID 12486434; Hermida-Prieto et al, 2005, PMID 15219508; van Tintelen et al, 2007, PMID 18035036; Moller et al, 2009, PMID 19875404; Botto et al, 2010, PMID 20307303; and others). Further, case-control data demonstrates enrichment of both truncating and non-truncating variants in the LMNA gene in cases relative to control subjects (Mazzarotto et al, 2020, PMID 31983221). In addition, this gene-disease assertion is supported by biochemical, protein interaction, functional alteration, expression studies and animal models. Several biochemical functional analyses have been performed showing abnormal nuclear morphology and protein localization in cell lines expressing mutated LMNA (Ostlund et al, 2001, PMID 11792809; Raharjo et al, 2001, PMID 11792810; Holt et al, 2003, PMID 12783988; Cowan et al, 2010, PMID 20160190). Protein interaction data has also been published, particularly in relation to loss and/or relocation of emerin (Raharjo et al, 2001, PMID 11792810; Holt et al, 2003, PMID 12783988). Knock-in mouse models (Mounkes et al, 2005, PMID 15972724) and knock-out (heterozygous) mouse models (Wolf et al, 2008, PMID 18182166) have demonstrated DCM phenotypes in these non-human model systems and experimental evidence in human cell lines have further supported this assertion (Dierks et al, 2010, PMID 19375354; Liu et al, 2020, PMID 31670395). Additional evidence is available in the literature beyond what is referenced here; however, the maximum score for genetic and experimental evidence has been reached. LMNA has also been curated by the Monogenic Diabetes Gene Curation Expert Panel for lipodystrophy (Definitive, 10/09/2024) and the Arrhythmogenic Right Ventricular Cardiomyopathy Gene Curation Expert Panel for ARVC (Limited, 09/06/2019). In summary, LMNA is definitively associated with autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on October 2, 2020 (SOP Version 7). This written summary was updated on 04/13/2025 and approved by the DCM GCEP on 05/30/2025.
Inheritance Pattern: AD
Disease ID:MONDO:0013178
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007269
Submitter: G2P
Inheritance Pattern: SD
Disease ID:MONDO:0006573
Submitter: ClinGen
Human pathogenic *LMNA* variants were first reported in association with autosomal dominant lipodystrophy in 1974 (Dunnigan et al, PMID 4362786). We have curated the inheritance pattern for *LMNA* related lipodystrophy as semidominant because, while most cases are autosomal dominant, a recessive mode of inheritance has been reported very rarely (Soyaltin et al, PMID:32685188, Savage et al, PMID:15298354, Le Dour et al, PMID:21346069). Both partial and complete loss of *LMNA* function due to heterozygous and homozygous or compound heterozygous variants in the *LMNA* have been reported. Typical autosomal dominant cases due to heterozygous variants present in exon 8 and 11 of *LMNA* with partial loss of subcutaneous limb and gluteal fat, insulin resistance, diabetes, hypertension and hypertriglyceridemia (Morel et al, PMID:16636128, Akinci et al, PMID:28641778). The occasional recessive cases due to homozygous or compound heterozygous variants are usually present with severe lipodystrophic syndrome with diabetes and /or acanthosis nigricans, liver steatosis, hypertriglyceridemia, lower serum leptin and adiponectin levels, and dilated cardiomyopathy with conduction disturbances (Le Dour et al, PMID:21346069, André et al PMID: 25819867, Treiber et al PMID: 34292171). At least 200 lipodystrophy - causing *LMNA* variants (primarily missense than frameshift or nonsense) have been reported in humans. Evidence supporting the association of this gene with lipodystrophy includes case level data, segregation data, and experimental data. The aggregated score for case-level and segregation data is 12 points. Of the over 200 reported, variants in this gene have been curated for this summary in 13 probands in 10 publications (PMIDs: 32686188,19201734, 18041775, 15298354, 16636128, 30177912, 28641778, 32524016, 21346069, 29108996) with 8 cases presenting as familial partial lipodystrophy and 5 cases with congenital generalized lipodystrophy. More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached; this has not been curated exhaustively. This gene-disease relationship is supported by functional assays, expression studies and functional alterations (Corsa CAS, et al, PMID:34088712, Friesen M et al, PMID:29108996, Fagerberg L et al, PMID:243099898, Wojtanik et al, PMID:19201734). Total points for the experimental evidence are 5.5. Total points for genetic and experimental evidence together are 17.5. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we observed both differences in inheritance pattern and phenotypic variability, but also overlap in the implicated variants. Specifically, *LMNA* has two associated lipodystrophy diseases entities, namely the more commonly associated autosomal dominant familial partial lipodystrophy (OMIM:151660), and the more rarely associated autosomal recessive congenital, generalized lipodystrophy. Because the latter is rare and there is overlap in the implicated variants, these two entities have been lumped in a single curation of lipodystrophy (MONDO: 0006573). In addition, *LMNA* has several other associated diseases, including but not limited to: dilated cardiomyopathy (MONDO: 0005021), arrhythmogenic right ventricular cardiomyopathy (ARVC; MONDO: 0016587), Charcot-Marie-Tooth disease (MIM: 5005588), Emery-Dreifuss muscular dystrophy (MIM: 181350 and 616516), and Hutchinson-Gilford progeria (MIM: 176670). While there is some genetic and phenotypic overlap, there is enough distinction among these phenotypes and their implicated variants that these entities have (dilated cardiomyopathy and ARVC) or will be curated separately. In summary, *LMNA* is definitively associated with semidominant lipodystrophy, with most cases presenting as autosomal dominant familial partial lipodystrophy in adolescents and young adults. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Endocrine; Hematologic; Musculoskeletal; Neurologic
Intervention: Cardiovascular
Rationale: Some LMNA-associated conditions can include cardiac anomalies, including arrhythmias and cardiomyopathy that can precede other obvious clinical signs/symptoms, and medical (eg, ICD placement) management prior to severe sequelae may be beneficial; In Hutchinson-Guilford Progeria, medical management (with farnesyltransferase inhibitors) has been shown to extend lifespan
Comments: Some allelic conditions are clinically recognizable, and in these, it is not clear if early (genetic) diagnosis would be additionally beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LMNA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_170707.4. 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 | 3 | 6 | 12 | 406 | 16 | 443 |
| missense | 83 | 264 | 856 | 15 | 1 | 1219 |
| nonsense | 52 | 17 | 5 | 74 | ||
| start loss | 6 | 2 | 8 | |||
| frameshift | 121 | 45 | 18 | 184 | ||
| splice donor/acceptor (+/-2bp) | 24 | 41 | 10 | 75 | ||
| Total | 289 | 375 | 901 | 421 | 17 | 2003 |
Highest pathogenic variant AF is 0.000042143987
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_733821.1 | 12 | MANE Select | |
| Ensembl | ENSP00000357283.4 | 12 | MANE Select | |
| RefSeq | NP_001244303.1 | 13 | Standard | |
| RefSeq | NP_001269553.1 | 10 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| lmna | Danio rerio | Structure: fat cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Dilated cardiomyopathy (DCM) - Homo sapiens (human)
- Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human)
- Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human)
- Apoptosis - Homo sapiens (human)
- Antiarrhythmic Pathway, Pharmacodynamics
Biological Process
- protein import into nucleus
- mitotic nuclear envelope reassembly
- negative regulation of cell population proliferation
- positive regulation of gene expression
- regulation of cell migration
Molecular Function
- structural molecule activity
- protein binding
Cellular Component
- nucleus
- nuclear envelope
- lamin filament
- nucleoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000368300
- Coding exons
- 12
- Length
- 57517
- Individuals with no LoFs
- 125729
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125732
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.37 | 269 | 403 | 0.668 | 0.0000276 | 4228 |
| Missense (PolyPhen) | 46 | 116.58 | 0.39457 | 1233 | ||
| Synonymous | 0.551 | 162 | 171 | 0.946 | 0.0000109 | 1367 |
| Loss of Function | 4.75 | 2 | 30.2 | 0.0663 | 0.00000158 | 338 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- 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. Lamin A and C are present in equal amounts in the lamina of mammals. Plays an important role in nuclear assembly, chromatin organization, nuclear membrane and telomere dynamics. Required for normal development of peripheral nervous system and skeletal muscle and for muscle satellite cell proliferation (PubMed:10080180, PubMed:22431096, PubMed:10814726, PubMed:11799477, PubMed:18551513). Required for osteoblastogenesis and bone formation (PubMed:12075506, PubMed:15317753, PubMed:18611980). Also prevents fat infiltration of muscle and bone marrow, helping to maintain the volume and strength of skeletal muscle and bone (PubMed:10587585). Required for cardiac homeostasis (PubMed:10580070, PubMed:12927431, PubMed:18611980, PubMed:23666920). {ECO:0000269|PubMed:10080180, ECO:0000269|PubMed:10580070, ECO:0000269|PubMed:10587585, ECO:0000269|PubMed:10814726, ECO:0000269|PubMed:11799477, ECO:0000269|PubMed:12075506, ECO:0000269|PubMed:12927431, ECO:0000269|PubMed:15317753, ECO:0000269|PubMed:18551513, ECO:0000269|PubMed:18611980, ECO:0000269|PubMed:22431096, ECO:0000269|PubMed:23666920}.;
- Disease
- DISEASE: Emery-Dreifuss muscular dystrophy 2, autosomal dominant (EDMD2) [MIM:181350]: A form of Emery-Dreifuss muscular dystrophy, a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system, early contractures of the elbows, Achilles tendons and spine, and cardiomyopathy associated with cardiac conduction defects. {ECO:0000269|PubMed:10080180, ECO:0000269|PubMed:10739764, ECO:0000269|PubMed:10908904, ECO:0000269|PubMed:10939567, ECO:0000269|PubMed:11503164, ECO:0000269|PubMed:11792809, ECO:0000269|PubMed:12032588, ECO:0000269|PubMed:12467752, ECO:0000269|PubMed:12649505, ECO:0000269|PubMed:14684700, ECO:0000269|PubMed:14985400, ECO:0000269|PubMed:15372542, ECO:0000269|PubMed:15744034, ECO:0000269|PubMed:19933576, ECO:0000269|PubMed:20848652}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Emery-Dreifuss muscular dystrophy 3, autosomal recessive (EDMD3) [MIM:616516]: A form of Emery-Dreifuss muscular dystrophy, a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system, early contractures of the elbows, Achilles tendons and spine, and cardiomyopathy associated with cardiac conduction defects. {ECO:0000269|PubMed:22431096, ECO:0000269|PubMed:27234031}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1A (CMD1A) [MIM:115200]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:10580070, ECO:0000269|PubMed:11561226, ECO:0000269|PubMed:11792809, ECO:0000269|PubMed:11897440, ECO:0000269|PubMed:12486434, ECO:0000269|PubMed:12628721, ECO:0000269|PubMed:12920062, ECO:0000269|PubMed:14675861, ECO:0000269|PubMed:14684700, ECO:0000269|PubMed:15140538, ECO:0000269|PubMed:15219508, ECO:0000269|PubMed:15372542, ECO:0000269|PubMed:16061563, ECO:0000269|PubMed:18606848, ECO:0000269|PubMed:19167105, ECO:0000269|PubMed:20160190, ECO:0000269|PubMed:21846512}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Lipodystrophy, familial partial, 2 (FPLD2) [MIM:151660]: A disorder characterized by the loss of subcutaneous adipose tissue in the lower parts of the body (limbs, buttocks, trunk). It is accompanied by an accumulation of adipose tissue in the face and neck causing a double chin, fat neck, or cushingoid appearance. Adipose tissue may also accumulate in the axillae, back, labia majora, and intraabdominal region. Affected patients are insulin-resistant and may develop glucose intolerance and diabetes mellitus after age 20 years, hypertriglyceridemia, and low levels of high density lipoprotein cholesterol. {ECO:0000269|PubMed:10587585, ECO:0000269|PubMed:10655060, ECO:0000269|PubMed:10739751, ECO:0000269|PubMed:11792809, ECO:0000269|PubMed:12015247, ECO:0000269|PubMed:12196663, ECO:0000269|PubMed:12629077, ECO:0000269|PubMed:15372542, ECO:0000269|PubMed:17250669, ECO:0000269|PubMed:19220582, ECO:0000269|PubMed:24485160}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Limb-girdle muscular dystrophy 1B (LGMD1B) [MIM:159001]: An autosomal dominant degenerative myopathy with age-related atrioventricular cardiac conduction disturbances, dilated cardiomyopathy, and the absence of early contractures. Characterized by slowly progressive skeletal muscle weakness of the hip and shoulder girdles. Muscle biopsy shows mild dystrophic changes. {ECO:0000269|PubMed:10814726, ECO:0000269|PubMed:11525883, ECO:0000269|PubMed:12032588, ECO:0000269|PubMed:12673789, ECO:0000269|PubMed:15372542, ECO:0000269|PubMed:15744034, ECO:0000269|PubMed:17136397, ECO:0000269|PubMed:27234031}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2B1 (CMT2B1) [MIM:605588]: A recessive axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:11799477}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hutchinson-Gilford progeria syndrome (HGPS) [MIM:176670]: Rare genetic disorder characterized by features reminiscent of marked premature aging. {ECO:0000269|PubMed:12714972, ECO:0000269|PubMed:12768443, ECO:0000269|PubMed:12927431, ECO:0000269|PubMed:15060110, ECO:0000269|PubMed:15286156, ECO:0000269|PubMed:15622532, ECO:0000269|PubMed:19933576, ECO:0000269|PubMed:21791255, ECO:0000269|PubMed:22355414, ECO:0000269|PubMed:23666920}. Note=The disease is caused by mutations affecting the gene represented in this entry. HGPS is caused by the toxic accumulation of a truncated form of lamin-A/C. This mutant protein, called progerin (isoform 6), acts to deregulate mitosis and DNA damage signaling, leading to premature cell death and senescence. The mutant form is mainly generated by a silent or missense mutation at codon 608 of prelamin A that causes activation of a cryptic splice donor site, resulting in production of isoform 6 with a deletion of 50 amino acids near the C terminus. Progerin lacks the conserved ZMPSTE24/FACE1 cleavage site and therefore remains permanently farnesylated. Thus, although it can enter the nucleus and associate with the nuclear envelope, it cannot incorporate normally into the nuclear lamina (PubMed:12714972). {ECO:0000269|PubMed:12714972}.; DISEASE: Cardiomyopathy, dilated, with hypergonadotropic hypogonadism (CMDHH) [MIM:212112]: A disorder characterized by the association of genital anomalies, hypergonadotropic hypogonadism and dilated cardiomyopathy. Patients can present other variable clinical manifestations including mental retardation, skeletal anomalies, scleroderma-like skin, graying and thinning of hair, osteoporosis. Dilated cardiomyopathy is characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. {ECO:0000269|PubMed:12927431, ECO:0000269|PubMed:17150192, ECO:0000269|PubMed:19283854}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mandibuloacral dysplasia with type A lipodystrophy (MADA) [MIM:248370]: A disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of the cranial suture, progeroid appearance, partial alopecia, soft tissue calcinosis, joint contractures, and partial lipodystrophy with loss of subcutaneous fat from the extremities. Adipose tissue in the face, neck and trunk is normal or increased. {ECO:0000269|PubMed:12075506, ECO:0000269|PubMed:15998779, ECO:0000269|PubMed:16278265}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Lethal tight skin contracture syndrome (LTSCS) [MIM:275210]: Rare disorder mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Liveborn children usually die within the first week of life. The overall prevalence of consanguineous cases suggested an autosomal recessive inheritance. {ECO:0000269|PubMed:15317753}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Heart-hand syndrome Slovenian type (HHS-Slovenian) [MIM:610140]: Heart-hand syndrome (HHS) is a clinically and genetically heterogeneous disorder characterized by the co- occurrence of a congenital cardiac disease and limb malformations. {ECO:0000269|PubMed:18611980}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muscular dystrophy congenital LMNA-related (MDCL) [MIM:613205]: A form of congenital muscular dystrophy. Patients present at birth, or within the first few months of life, with hypotonia, muscle weakness and often with joint contractures. {ECO:0000269|PubMed:18551513}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in LMNA may cause a late-onset cardiocutaneous progeria syndrome characterized by cutaneous manifestations of aging appearing in the third decade of life, cardiac valve calcification and dysfunction, prominent atherosclerosis, and cardiomyopathy, leading to death on average in the fourth decade. {ECO:0000269|PubMed:23666920}.;
Recessive Scores
- pRec
- 0.986
Intolerance Scores
- LoFtool
- 0.00103
- RVIS EVS
- -0.91
- RVIS percentile EVS
- 9.96
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.998
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |