Submission Details

BAG3 was originally evaluated for DCM by ClinGen DCM GCEP on September 24, 2020. Evidence of the association of this gene with DCM was re-evaluated on 04/09/2025. 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.

BAG3 was first reported in relation to autosomal dominant dilated cardiomyopathy in 2011 (Norton et al., 2011, PMID: 21353195). At least 16 unique variants including missense, in-frame indel, nonsense and frameshift variants, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, case-control data, segregation data and experimental data. Variants in this gene have been reported in at least 20 probands in 8 primary publications (PMIDs 21353195, 25008357, 25448463, 24623017, 27391596, 28211974, 30442290, 31983221). Variants in this gene segregate with disease in >100 additional family members. This gene-disease relationship has been studied in at least one case-control study (PMID 31983221) at the aggregate variant level, where BAG3 truncating variants were enriched in two DCM cohorts vs primary and ExAC control populations. The reported etiologic fraction for truncating variants was 0.98 and >0.99 for the primary and secondary cohorts respectively. In addition, this gene-disease association is supported by multiple animal models (mouse and zebrafish), human iPS cell culture models, in vitro functional assays, and expression studies. BAG3 was shown to be expressed in human and mouse heart tissues (Homma et al., 2006, PMID: 16936253). BAG3 protein levels were noted to be reduced in heart failure patients and individuals with BAG3 genetic variants (Feldman et al., 2014, PMID: 24623017 and Toro et al., 2016, PMID: 27391596). Heterozygous cardiomyocyte-specific BAG3 knockout or BAG3 E455K knock-in mouse models both developed DCM phenotypes (Fang et al., 2017, PMID: 28737513 and Myers et al., 2018, PMID: 29323723). Additional evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached.BAG3 has also been curated by the General Gene Curation Expert Panel for myofibrillar myopathy (Definitive, 12/18/2016). In summary, BAG3 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 originally approved by the ClinGen Dilated Cardiomyopathy Working Group on September 24, 2020 (SOP Version 7). This written summary was updated on 04/09/2025 and approved by the DCM GCEP on 05/30/2025.