ClinVar Genomic variation as it relates to human health
NM_004281.4(BAG3):c.1363G>A (p.Glu455Lys)
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.1363G>A (p.Glu455Lys)
Variation ID: 44778 Accession: VCV000044778.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q26.11 10: 119676917 (GRCh38) [ NCBI UCSC ] 10: 121436429 (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 Apr 6, 2024 Mar 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004281.4:c.1363G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004272.2:p.Glu455Lys missense NC_000010.11:g.119676917G>A NC_000010.10:g.121436429G>A NG_016125.1:g.30548G>A LRG_742:g.30548G>A LRG_742t1:c.1363G>A LRG_742p1:p.Glu455Lys O95817:p.Glu455Lys - Protein change
- E455K
- Other names
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- Canonical SPDI
- NC_000010.11:119676916:G:A
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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.
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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
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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
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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) |
criteria provided, single submitter
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Aug 7, 2017 | RCV000037887.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 19, 2023 | RCV000230332.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 17, 2021 | RCV000255835.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 26, 2020 | RCV002381307.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 25, 2024 | RCV003989304.1 |
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
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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
(Feb 21, 2017)
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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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Blueprint Genetics
Accession: SCV000927163.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 |
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Pathogenic
(Aug 26, 2020)
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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: SCV002702132.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.E455K pathogenic mutation (also known as c.1363G>A), located in coding exon 4 of the BAG3 gene, results from a G to A substitution at … (more)
The p.E455K pathogenic mutation (also known as c.1363G>A), located in coding exon 4 of the BAG3 gene, results from a G to A substitution at nucleotide position 1363. The glutamic acid at codon 455 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in individuals with dilated cardiomyopathy (DCM), and shown to segregate with disease in multiple families (Villard E et al. Eur Heart J. 2011;32(9):1065-76; Dominguez et al. J Am Coll Cardiol. 2018;72(20):2471-2481; Franaszczyk M et al. J Transl Med. 2014;12:192). Furthermore, mice with cardiac-specific BAG3 knockdown or cardiac-specific BAG3-E455K knock-in developed DCM; decreased levels of small heat shock proteins were observed, and the E455K-BAG3 protein demonstrated defective interaction with HSP70, consistent with loss-of-function as the mechanism of disease (Fang X et al. J. Clin. Invest., 2017 Aug;127:3189-3200). In addition, other loss of function alterations in the BAG domain have been reported with strong segregation in numerous cases of familial DCM (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; Franaszczyk M et al. J Transl Med. 2014;12:192). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 07, 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: SCV000061549.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Glu455Lys variant in BAG3 has been identified in 4 individuals with DCM, s egregated with disease in 6 affected relatives from 3 families (Villard … (more)
The p.Glu455Lys variant in BAG3 has been identified in 4 individuals with DCM, s egregated with disease in 6 affected relatives from 3 families (Villard 2011, Fr anaszczyk 2014, LMM unpublished data), and was absent from large population stud ies. Additionally, a mouse model harboring this variant presented with DCM (Fang 2017). In summary, this variant meets criteria to be classified as pathogenic f or DCM in an autosomal dominant manner based upon segregation studies, absence f rom controls, and functional evidence. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 17, 2021)
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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: SCV000321414.8
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21459883, 25008357, 22337857, 27474739, 28737513, 31737537, 32458740, 32472079) (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: SCV000288297.7
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 455 of the BAG3 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 455 of the BAG3 protein (p.Glu455Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 2159883, 25008357). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44778). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BAG3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Myofibrillar myopathy 6
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806149.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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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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Retrospective Analysis of Clinical Genetic Testing in Pediatric Primary Dilated Cardiomyopathy: Testing Outcomes and the Effects of Variant Reclassification. | Quiat D | Journal of the American Heart Association | 2020 | PMID: 32458740 |
Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations. | Domínguez F | Journal of the American College of Cardiology | 2018 | PMID: 30442290 |
Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy. | Fang X | The Journal of clinical investigation | 2017 | PMID: 28737513 |
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 |
Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era. | Norton N | Circulation. Cardiovascular genetics | 2012 | PMID: 22337857 |
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 |
Activation of multiple signal transduction pathways by endothelin in cultured human vascular smooth muscle cells. | Resink TJ | European journal of biochemistry | 1990 | PMID: 2159883 |
Text-mined citations for rs397516881 ...
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.