ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.699C>A (p.Tyr233Ter) (rs876661342)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463650 SCV000550825 pathogenic Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-08-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr233*) in the BAG3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 234982). Loss-of-function variants in BAG3 are known to be pathogenic (PMID: 21353195, 25008357). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000223884 SCV000564689 pathogenic not provided 2018-02-23 criteria provided, single submitter clinical testing Although the Y233X variant in the BAG3 gene has not been published as pathogenic or been reported as benign to our knowledge, it has been identified in other individuals referred for cardiomyopathy genetic testing at GeneDx. Y233X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the BAG3 gene have been reported in Human Gene Mutation Database in association with DCM (Stenson et al., 2014). Furthermore, the Y233X variant is not observed in large population cohorts (Lek et al., 2016).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223884 SCV000280054 likely pathogenic not provided 2015-07-22 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the data supporting pathogenicity of nonsense BAG3 variants, the case data, and the absence in patients unselected for cardiomyopathy, we consider this variant likely disease causing. This specific variant (p.Tyr233Ter) is novel. However, it has been seen in one of the families reported in an initial publication on BAG3 (Norton et al 2011). That family had two brothers with DCM and both had this variant and p.Ala262Thr in BAG3. No phase data is available. 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 July 14th, 2015).

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