Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001240816 | SCV001413791 | pathogenic | Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH | 2023-12-12 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gly25Argfs*33) in the BAG3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BAG3 are known to be pathogenic (PMID: 21353195, 25008357). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with BAG3-related conditions (PMID: 30442290). ClinVar contains an entry for this variant (Variation ID: 966196). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002379920 | SCV002670982 | pathogenic | Cardiovascular phenotype | 2021-08-03 | criteria provided, single submitter | clinical testing | The c.72dupC pathogenic mutation, located in coding exon 1 of the BAG3 gene, results from a duplication of C at nucleotide position 72, causing a translational frameshift with a predicted alternate stop codon (p.G25Rfs*33). This variant has been detected in individuals from a dilated cardiomyopathy cohort (Domínguez F et al. J Am Coll Cardiol, 2018 11;72:2471-2481). Loss of function alterations have been reported in numerous cases of familial dilated cardiomyopathy, including many families with strong segregation with disease (Norton N et al. Am J Hum Genet. 2011;88(3):273-82; Villard E et al. Eur Heart J. 2011;32(9):1065-76; Chami N et al. Can J Cardiol. 2014;30(12):1655-61; Feldman AM et al. J Cell Physiol. 2014;229(11):1697-702; Franaszczyk M et al. J Transl Med. 2014;12:192; van Spaendonck-Zwarts KY et al. Eur Heart J. 2014;35(32):2165-73). In addition, in Norton et al. 2011, BAG3 knockdown in a zebrafish model showed heart failure with decreased fractional shortening and pericardial effusion. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
| Gene |
RCV001780179 | SCV002770287 | likely pathogenic | not provided | 2023-07-12 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in association with DCM, though patient-specific clinical details are lacking (Domnguez et al., 2018); This variant is associated with the following publications: (PMID: 30442290) |