ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.925C>T (p.Arg309Ter) (rs869248137)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000459684 SCV000893147 pathogenic Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000414723 SCV000490423 pathogenic not provided 2018-11-05 criteria provided, single submitter clinical testing The R309X pathogenic variant in the BAG3 gene has been published in association with familial DCM (Villard et al., 2011; Chami et al., 2014). Together, Villard et al. (2011) and Chami et al. (2014) reported that the R309X variant segregated with disease in over 15 affected relatives from four unrelated families. In addition, R309X has been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and it segregated with a DCM phenotype in multiple relatives from one family. Furthermore, R309X is classified in ClinVar as a pathogenic variant by other clinical laboratories in association with DCM (SCV000271310.2, SCV000550839.2, SCV000740456.1; Landrum et al., 2016). The R309X variant is predicted to cause loss of normal protein function by protein truncation, in which the last 267 amino acid residues are lost. Other nonsense variants in the BAG3 gene as well as multiple missense variants in the deleted region have been reported in Human Gene Mutation Database in association with DCM (Stenson et al., 2014). Moreover, R309X is not observed in large population cohorts (Lek et al., 2016).
Invitae RCV000459684 SCV000550839 pathogenic Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-02-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BAG3 gene (p.Arg309*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 267 amino acids of the BAG3 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with dilated cardiomyopathy in several families (PMID: 25448463). ClinVar contains an entry for this variant (Variation ID: 228322). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000215224 SCV000271310 pathogenic Primary dilated cardiomyopathy 2015-09-24 criteria provided, single submitter clinical testing The p.Arg309X variant in BAG3 has been previously reported in 5 individuals with DCM (Villard 2011, Chami 2014, LMM unpublished data) and segregated with the di sease in greater than 15 affected family members (Chami 2014). It was absent fro m large population studies. This nonsense variant leads to a premature terminati on codon at position 309. Based on its position (last exon), it is predicted to result in a truncated protein rather than case loss of function. In summary, th is variant meets our criteria to be classified as pathogenic for DCM in an autos omal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based up on segregation studies and absence from controls.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000623366 SCV000740456 pathogenic Familial dilated cardiomyopathy 2016-04-26 criteria provided, single submitter clinical testing

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