Submissions for variant NM_004281.4(BAG3):c.77G>A (p.Trp26Ter)

dbSNP: rs1554875409

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000615326	SCV000712370	likely pathogenic	Primary dilated cardiomyopathy	2016-07-18	criteria provided, single submitter	clinical testing	The p.Trp26X variant in BAG3 has not been previously reported in individuals wit h cardiomyopathy or in large population studies. This nonsense variant leads to a premature termination codon at position 26, which is predicted to lead to a tr uncated or absent protein. Loss-of-function variants in BAG3 are associated with DCM (Knezevic, 2015). In summary, although additional studies are required to f ully establish its clinical significance, the p.Trp26X variant is likely pathoge nic.
GeneDx	RCV001008646	SCV001168421	pathogenic	not provided	2023-06-16	criteria provided, single submitter	clinical testing	Identified in a patient with DCM and several affected family members in the published literature, as well as in patients with DCM and their relatives referred for cardiogenetic testing at GeneDx (PMID: 28436997); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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; This variant is associated with the following publications: (PMID: 28436997)
Ambry Genetics	RCV002413693	SCV002674736	likely pathogenic	Cardiovascular phenotype	2022-08-16	criteria provided, single submitter	clinical testing	The p.W26* variant (also known as c.77G>A), located in coding exon 1 of the BAG3 gene, results from a G to A substitution at nucleotide position 77. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. The predicted stop codon occurs in the 5’ end of theBAG3 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This alteration has been reported in an individual with dilated cardiomyopathy (DCM) (Janin A et al. Clin Genet, 2017 Dec;92:616-623). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002483674	SCV002784157	likely pathogenic	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2021-07-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV003389249	SCV004101369	likely pathogenic	Dilated cardiomyopathy 1HH	2023-09-07	criteria provided, single submitter	clinical testing	The BAG3 c.77G>A (p.Trp26Ter) nonsense variant is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD) is expected; however, this variant occurs within 100bp of the initiation codon, a region in which NMD is known to occur with reduced efficiency (PMID: 27618451; 33277042). This variant has been identified in an individual with dilated cardiomyopathy (PMID: 28436997). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been classified as pathogenic or likely pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.77G>A (p.Trp26Ter) variant is classified as likely pathogenic for dilated cardiomyopathy.
Invitae	RCV002483674	SCV004569715	pathogenic	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2023-09-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp26*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 28436997). ClinVar contains an entry for this variant (Variation ID: 505229). For these reasons, this variant has been classified as Pathogenic.