ClinVar Miner

Submissions for variant NM_004281.4(BAG3):c.1363G>A (p.Glu455Lys) (rs397516881)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037887 SCV000061549 pathogenic Primary dilated cardiomyopathy 2017-08-07 criteria provided, single submitter clinical testing The p.Glu455Lys variant in BAG3 has been identified in 4 individuals with DCM, s egregated with disease in 6 affected relatives from 3 families (Villard 2011, Fr anaszczyk 2014, LMM unpublished data), and was absent from large population stud ies. Additionally, a mouse model harboring this variant presented with DCM (Fang 2017). In summary, this variant meets criteria to be classified as pathogenic f or DCM in an autosomal dominant manner based upon segregation studies, absence f rom controls, and functional evidence.
Invitae RCV000230332 SCV000288297 pathogenic Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-01-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 455 of the BAG3 protein (p.Glu455Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with dilated cardiomyopathy in two unrelated families (PMID: 2159883, 25008357). In addition, this variant was identified in an unrelated individual with dilated cardiomyopathy (PMID: 25008357). ClinVar contains an entry for this variant (Variation ID: 44778). In summary, this variant is absent from population databases and has been shown to segregate with dilated cardiomyopathy in multiple affected individuals. For these reasons, this has been classified as Pathogenic.
GeneDx RCV000255835 SCV000321414 likely pathogenic not provided 2016-12-22 criteria provided, single submitter clinical testing The E455K likely pathogenic variant in the BAG3 gene has been reported previously to be co-segregating with a DCM phenotype in three unrelated families, and was absent from approximately 1,200 healthy control alleles (Villard et al., 2011; Franaszczyk et al., 2014). This variant has also been reported in one other individual tested for cardiomyopathy at GeneDx and was found to co-segregate with cardiomyopathy in one relative. Furthermore, the E455K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. E455K results in a non-conservative amino acid, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and occurs at a position that is conserved across species. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Blueprint Genetics RCV000255835 SCV000927163 pathogenic not provided 2017-02-21 criteria provided, single submitter clinical testing

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