ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.1067del (p.Pro356fs) (rs727505109)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476824 SCV000550844 likely pathogenic Dilated cardiomyopathy 1HH 2016-06-02 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 4 of the BAG3 mRNA (c.1067delC), causing a frameshift at codon 356. This creates a premature translational stop signal in the last exon of the BAG3 mRNA (p.Pro356Hisfs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated BAG3 protein. This variant is not present in population databases (rs727505109, ExAC no frequency) and has not been reported in the literature in individuals with a BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 179764). A different truncation downstream of this position (p.Leu423Lysfs*14) is reported to be deleterious (PMID: 24623017). This indicates that the truncation affects residues that are important for BAG3 protein function. In the absence of additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156562 SCV000206281 likely pathogenic Primary dilated cardiomyopathy 2016-04-15 criteria provided, single submitter clinical testing The p.Pro356fs variant in BAG3 has been identified by our laboratory in 1 Caucas ian individual with DCM. It was absent from large population studies. This varia nt is predicted to cause a frameshift, which alters the protein?s amino acid seq uence beginning at position 356 and leads to a premature termination codon 7 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of functions variants in BAG3 have been reported to be dis ease-causing (Norton 2011, Villard, 2011). In summary, although additional studi es are required to fully establish its clinical significance, the p.Pro356fs var iant is likely pathogenic.

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