Submission Details

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.