ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.100_107del (p.Thr34fs) (rs727505283)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156812 SCV000206533 likely pathogenic Primary dilated cardiomyopathy 2017-03-23 criteria provided, single submitter clinical testing The p.Thr34AlafsX21 variant in BAG3 has been identified in 2 siblings with DCM ( LMM data) and was absent from large population studies, though the ability of th ese studies to accurately detect indels may be limited. This variant is predicte d to cause a frameshift, which alters the protein?s amino acid sequence beginnin g at position 34 and leads to a premature termination codon 21 amino acids downs tream. This alteration is then predicted to lead to a truncated or absent protei n. Loss-of-function variants in BAG3 have been reported to be disease-causing (K nezevic 2015). In summary, although additional studies are required to fully est ablish its clinical significance, the p.Thr34AlafsX21 variant is likely pathogen ic. ACMG/AMP Criteria applied: PVS1_Strong, PM2.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786108 SCV000924756 likely pathogenic not provided 2017-01-03 no assertion criteria provided provider interpretation Given the strong evidence implicating frameshift variants in BAG3 in disease and the rarity of the variant, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There are no published reports of the variant. The normal sequence with the bases that are deleted in braces is: GCAG[ACCGGCTG]GCCC. Given how early on the variant occurs it most likely leads to nonsense mediated decay and no protein product. As reviewed above, null variants in BAG3 have been implicated in disease and are very rare in the general population. The variant is not listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 24th, 2015). However, the methods used with that dataset may miss some indels of this size. The variant was also absent in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. As with ExAC, it is unclear how well the methods used in that dataset account for potential indels.

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