ClinVar Genomic variation as it relates to human health
NM_004281.4(BAG3):c.211C>T (p.Arg71Trp)
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.
Uncertain significance(2); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004281.4(BAG3):c.211C>T (p.Arg71Trp)
Variation ID: 30396 Accession: VCV000030396.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q26.11 10: 119669881 (GRCh38) [ NCBI UCSC ] 10: 121429393 (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 Dec 26, 2017 Feb 28, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004281.4:c.211C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004272.2:p.Arg71Trp missense NC_000010.11:g.119669881C>T NC_000010.10:g.121429393C>T NG_016125.1:g.23512C>T LRG_742:g.23512C>T LRG_742t1:c.211C>T LRG_742p1:p.Arg71Trp O95817:p.Arg71Trp - Protein change
- R71W
- Other names
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- Canonical SPDI
- NC_000010.11:119669880: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00014
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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
Help
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
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 (1) |
no assertion criteria provided
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Mar 11, 2011 | RCV000023349.11 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 2, 2024 | RCV000456156.19 | |
Likely benign (2) |
criteria provided, single submitter
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May 14, 2019 | RCV000852638.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 25, 2020 | RCV001811196.13 | |
Likely benign (1) |
criteria provided, single submitter
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May 4, 2023 | RCV002415426.9 | |
Likely benign (1) |
criteria provided, single submitter
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May 16, 2023 | RCV003234916.8 |
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
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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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Uncertain significance
(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: SCV000894521.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Oct 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002048838.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The BAG3 c.211C>T; p.Arg71Trp variant (rs387906874) is reported in the literature in several individuals affected with cardiomyopathy (Norton 2011, Cowan 2018, van Lint 2019). This … (more)
The BAG3 c.211C>T; p.Arg71Trp variant (rs387906874) is reported in the literature in several individuals affected with cardiomyopathy (Norton 2011, Cowan 2018, van Lint 2019). This variant is also reported in ClinVar (Variation ID: 30396). This variant is found in the Finnish European population with an allele frequency of 0.07% (17/25104 alleles) in the Genome Aggregation Database. The arginine at codon 71 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.37). Due to limited information, the clinical significance of the p.Arg71Trp variant is uncertain at this time. Pathogenic variants in BAG3 are associated with autosomal dominant dilated cardiomyopathy 1HH (MIM: 613881) and myofibrillar myopathy 6 (MIM: 612954). References: Norton et al. Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am J Hum Genet. 2011 Mar 11;88(3):273-82. Cowan et al. Multigenic Disease and Bilineal Inheritance in Dilated Cardiomyopathy Is Illustrated in Nonsegregating LMNA Pedigrees. Circ Genom Precis Med. 2018 Jul;11(7):e002038. van Lint et al. Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. Neth Heart J. 2019 Jun;27(6):304-309. (less)
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Likely benign
(May 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003933745.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: BAG3 c.211C>T (p.Arg71Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: BAG3 c.211C>T (p.Arg71Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251304 control chromosomes (gnomAD). The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in BAG3 causing Dilated Cardiomyopathy phenotype (3.9e-05), strongly suggesting that the variant is benign. c.211C>T has been reported in the literature in two individuals affected with Dilated Cardiomyopathy from the same family, however both also shared variants in other cardiac-related genes (Norton_2011, Cowan_2018). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. The variant has also been reported in an individual with an unknown/unspecified cardiomyopathy who had a co-occurring pathogenic variant in MYBPC3 (c.1505G>A, p.Arg502Gln), providing supporting evidence for a benign role (van Lint_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30012837, 21353195, 30847666). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=3) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Jan 02, 2024)
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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: SCV000550833.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
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Likely benign
(May 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
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Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995343.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 1
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Likely benign
(May 04, 2023)
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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: SCV002725290.2
First in ClinVar: Nov 29, 2022 Last updated: Jul 08, 2023 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (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: SCV000044640.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 26, 2017 |
Comment on evidence:
In a mother and son who were diagnosed with dilated cardiomyopathy (CMD1HH; 613881) at ages 59 years and 41 years, respectively, Norton et al. (2011) … (more)
In a mother and son who were diagnosed with dilated cardiomyopathy (CMD1HH; 613881) at ages 59 years and 41 years, respectively, Norton et al. (2011) identified heterozygosity for a 211C-T transition in exon 2 of the BAG3 gene, resulting in an arg71-to-trp (R71W) substitution. The mutation was not found in 2,644 control chromosomes. The mother underwent heart transplant at age 65 years. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: research
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Dilated Cardiomyopathy
Affected status: yes
Allele origin:
inherited
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001434726.1
First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
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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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Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Multigenic Disease and Bilineal Inheritance in Dilated Cardiomyopathy Is Illustrated in Nonsegregating LMNA Pedigrees. | Cowan JR | Circulation. Genomic and precision medicine | 2018 | PMID: 30012837 |
Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era. | Norton N | Circulation. Cardiovascular genetics | 2012 | PMID: 22337857 |
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 rs387906874 ...
HelpRecord last updated Apr 20, 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.