LMNA
Chr 1ADARlamin A/C
Also known as: CDCD1, CDDC, CMD1A, CMT2B1, EMD2, FPL, FPLD, FPLD2
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]
Definitive — sufficient evidence for diagnostic panels
3 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Moderately missense-constrained (top ~2.5%)
Lamin A/C. DN missense variants cause EDMD, dilated cardiomyopathy, lipodystrophy, and progeria. LOF (haploinsufficiency) also causes dilated cardiomyopathy. Biallelic LOF causes restrictive dermopathy. Mechanism is variant- and phenotype-dependent.12
This gene — mechanism propensity
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
References
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
LMNA · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Observatoire Des Patients Atteints de Laminopathies et Emerinopathies (Observatory for PAtients With Laminopathies and Emerinopathies)
RECRUITINGIdentification of Women With Severe Insulin Resistant Syndromes of Genetic Origin Among Patients With "Classic" Polycystic Ovary Syndrome (PCOS)
NOT YET RECRUITINGAssess the Possibility of Diagnosing Diabetes and Rediabetes Following Oral Induced Hyperglycemia in Patients With Dunnigan's Partial Familial Lipodystrophy by Replacing 75 g of Glucose With a Standardized Carbohydrate Breakfast and Continuous Interstitial Monitoring Glucose)
RECRUITINGThe LD Lync Study - Natural History Study of Lipodystrophy Syndromes
RECRUITINGTissue and Metabolic Characterization of Arrhythmogenic Cardiomyopathies by Hybrid PET-MRI Imaging, Impact of the Observed Profiles on the Phenotype and on the Evolution of Cardiomyopathy
RECRUITINGBiomarkers in SCOTland CardiomyopatHy Registry (Bio-SCOTCH)
RECRUITINGModifying Factors in Striated Muscle Laminopathies
RECRUITINGExternal Resources
Links to major genomics databases and tools