ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.