ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 10q26.11
  • GRCh37/hg19 chr10: 121,410,882-121,437,331
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr10: 119,651,380-119,677,819
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000010.10) (NC_000010.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
21353195 Norton et al. (2011) performed whole-genome array and whole-exome sequencing on a multigenerational family affected with familial autosomal dominant dilated cardiomyopathy (DCM) and identified an 8.7 kb deletion including exon 4 present in all 7 family members and absent from 355 controls. Targeted sequencing of exons 2-4 on a cohort of 311 additional DCM patients identified one frameshift, two nonsense, and four missense heterozygous mutations all predicted to result in loss-of-function in 7 unrelated probands; these mutations were also absent from 355 controls. Knockdown studies in zebrafish supported the data. This study has also been reviewed in OMIM (see
25008357 Franaszczyk et al. (2014) performed direct sequencing of exons and splice sites of BAG3 on a cohort of 90 DCM patients and identified 3 missense mutations, one nonsense mutation, and a 17.9 kb deletion encompassing exons 3-4 in 6 unrelated probands.
21459883 Villard et al. (2011) performed BAG3 exome sequencing in a cohort of 168 patients with DCM and identified 4 nonsense and two missense mutations in 6 probands. Each mutation was heterozygous and present in all affected relatives of the probands and absent from 347 healthy controls.

Haploinsufficiency phenotype comments:

Heterozygous mutations and intragenic deletions affecting BAG3 have been identified in multiple unrelated patients with dilated cardiomyopathy (DCM). There are some reports of normal echo/ECG in BAG3 mutation carriers, suggestive of incomplete penetrance (see PMID 25008357, 21459883). Of the two families with intragenic BAG3 deletions, all carriers were shown to be affected.Functional studies support some of these findings (see and PMID 21353195, 25008357, 21898660, 21459883). As yet, whole BAG3 deletions have not been reported Additionally, p.P209 mutations have been reported in association with myofibrillar myopathy (see PMID 19085932, 21361913, 25208129).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity