ClinVar Genomic variation as it relates to human health
NM_004281.4(BAG3):c.367C>T (p.Arg123Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004281.4(BAG3):c.367C>T (p.Arg123Ter)
Variation ID: 30397 Accession: VCV000030397.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q26.11 10: 119670037 (GRCh38) [ NCBI UCSC ] 10: 121429549 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 8, 2017 Feb 28, 2024 Dec 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004281.4:c.367C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004272.2:p.Arg123Ter nonsense NC_000010.11:g.119670037C>T NC_000010.10:g.121429549C>T NG_016125.1:g.23668C>T LRG_742:g.23668C>T LRG_742t1:c.367C>T LRG_742p1:p.Arg123Ter - Protein change
- R123*
- Other names
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- Canonical SPDI
- NC_000010.11:119670036:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BAG3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1091 | 1127 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 3, 2022 | RCV000023350.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 27, 2017 | RCV000211711.5 | |
Pathogenic (2) |
criteria provided, single submitter
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Mar 31, 2023 | RCV000254992.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 11, 2022 | RCV000247382.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2023 | RCV000627789.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000318449.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Mar 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000322083.10
First in ClinVar: Oct 09, 2016 Last updated: Apr 09, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Myofibrillar myopathy 6
Dilated cardiomyopathy 1HH
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893146.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Jan 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061554.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 5
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Pathogenic
(Nov 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1HH
Affected status: unknown
Allele origin:
germline
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DASA
Accession: SCV002588785.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
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Pathogenic
(Apr 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1HH
Affected status: yes
Allele origin:
paternal
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921919.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
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) … (more)
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 (less)
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Pathogenic
(Dec 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1HH
Myofibrillar myopathy 6
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000550842.9
First in ClinVar: May 29, 2016 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 11, 2011)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, DILATED, 1HH
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044641.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 26, 2017 |
Comment on evidence:
In a brother and sister who were diagnosed with dilated cardiomyopathy (CMD1HH; 613881) at ages 25 years and 34 years, respectively, Norton et al. (2011) … (more)
In a brother and sister who were diagnosed with dilated cardiomyopathy (CMD1HH; 613881) at ages 25 years and 34 years, respectively, Norton et al. (2011) identified heterozygosity for a 367C-T transition in exon 2 of the BAG3 gene, resulting in an arg123-to-ter (R123X) substitution. The mutation was present in their father, who had undergone a heart transplant for an unknown type of cardiomyopathy at 40 years of age, and was also present in an asymptomatic sister, but was not found in 2,644 control chromosomes. The brother had undergone heart transplant at 26 years of age, but his affected sister had only mild left ventricular dysfunction. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Dilated cardiomyopathy 1HH
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760248.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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Likely pathogenic
(Jan 29, 2018)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924755.1
First in ClinVar: Jul 01, 2019 Last updated: Jul 01, 2019 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Truncating mutations on myofibrillar myopathies causing genes as prevalent molecular explanations on patients with dilated cardiomyopathy. | Janin A | Clinical genetics | 2017 | PMID: 28436997 |
BAG3 myofibrillar myopathy presenting with cardiomyopathy. | Konersman CG | Neuromuscular disorders : NMD | 2015 | PMID: 25728519 |
Nonsense mutations in BAG3 are associated with early-onset dilated cardiomyopathy in French Canadians. | Chami N | The Canadian journal of cardiology | 2014 | PMID: 25448463 |
The BAG3 gene variants in Polish patients with dilated cardiomyopathy: four novel mutations and a genotype-phenotype correlation. | Franaszczyk M | Journal of translational medicine | 2014 | PMID: 25008357 |
Decreased levels of BAG3 in a family with a rare variant and in idiopathic dilated cardiomyopathy. | Feldman AM | Journal of cellular physiology | 2014 | PMID: 24623017 |
Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy. | van Spaendonck-Zwarts KY | European heart journal | 2014 | PMID: 24558114 |
A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy. | Villard E | European heart journal | 2011 | PMID: 21459883 |
Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. | Norton N | American journal of human genetics | 2011 | PMID: 21353195 |
Text-mined citations for rs387906875 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.