Submissions for variant NM_004281.4(BAG3):c.367C>T (p.Arg123Ter)

gnomAD frequency: 0.00001  dbSNP: rs387906875

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211711	SCV000061554	likely pathogenic	Primary dilated cardiomyopathy	2017-01-27	criteria provided, single submitter	clinical testing	The p.Arg123X variant in BAG3 has been identified in 4 adults with DCM and segre gated with disease in 5 affected relatives (Norton 2011, LMM data). This variant has also been identified in 2/66492 European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs387906875). This no nsense variant leads to a premature termination codon at position 123, which is predicted to lead to a truncated or absent protein. Loss of function variants in BAG3 are strongly associated with DCM. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg123X variant is likely pathogenic.
Ambry Genetics	RCV000247382	SCV000318449	pathogenic	Cardiovascular phenotype	2022-08-11	criteria provided, single submitter	clinical testing	The p.R123* pathogenic mutation (also known as c.367C>T), located in coding exon 2 of the BAG3 gene, results from a C to T substitution at nucleotide position 367. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been reported in individuals with dilated cardiomyopathy (DCM) (Norton N et al. Am J Hum Genet. 2011;88(3):273-82; Janin A et al. Clin. Genet., 2017. Dec;92(6):616-23). In addition to the clinical data presented in the literature, 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.
GeneDx	RCV000254992	SCV000322083	pathogenic	not provided	2023-03-31	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28724793, 25008357, 21459883, 24623017, 24558114, 34935411, 34758253, 25525159, 25728519, 28436997, 25448463, 27391596, 31514951, 32859500, 21353195, 35653365, 33996946, 31983221)
Invitae	RCV000627789	SCV000550842	pathogenic	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg123*) 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 present in population databases (rs387906875, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 21353195, 25008357). ClinVar contains an entry for this variant (Variation ID: 30397). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000627789	SCV000893146	pathogenic	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2018-10-31	criteria provided, single submitter	clinical testing
DASA	RCV000023350	SCV002588785	pathogenic	Dilated cardiomyopathy 1HH	2022-11-03	criteria provided, single submitter	clinical testing	The c.367C>T;p.Arg123* variant creates a premature translational stop signal in the BAG3 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 30397; PMID: 28436997) - PS4. The variant is present at low allele frequencies population databases (rs387906875 – gnomAD 0.00007955%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000023350	SCV003921919	pathogenic	Dilated cardiomyopathy 1HH	2022-04-01	criteria provided, single submitter	clinical testing	0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with dilated cardiomyopathy, 1HH (MIM#613881) and myofibrillar myopathy, 6 (MIM#612954). Variants resulting in a premature stop codon are reported to have a loss of function mechanism, whereas missense variants have a gain of function effect (PMID: 27321750). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMIDs: 30442290, 33989081). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and consistently observed in individuals with dilated cardiomyopathy (ClinVar, PMID: 34935411). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000023350	SCV000044641	pathogenic	Dilated cardiomyopathy 1HH	2011-03-11	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000254992	SCV000924755	likely pathogenic	not provided	2018-01-29	no assertion criteria provided	provider interpretation
Genomics England Pilot Project, Genomics England	RCV000023350	SCV001760248	likely pathogenic	Dilated cardiomyopathy 1HH		no assertion criteria provided	clinical testing