ClinVar Genomic variation as it relates to human health
NM_004281.4(BAG3):c.626C>T (p.Pro209Leu)
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.626C>T (p.Pro209Leu)
Variation ID: 5981 Accession: VCV000005981.63
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q26.11 10: 119672373 (GRCh38) [ NCBI UCSC ] 10: 121431885 (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 Apr 4, 2013 Oct 20, 2024 Dec 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004281.4:c.626C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004272.2:p.Pro209Leu missense NC_000010.11:g.119672373C>T NC_000010.10:g.121431885C>T NG_016125.1:g.26004C>T LRG_742:g.26004C>T LRG_742t1:c.626C>T LRG_742p1:p.Pro209Leu O95817:p.Pro209Leu - Protein change
- P209L
- Other names
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p.P209L:CCG>CTG
- Canonical SPDI
- NC_000010.11:119672372: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.
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- Links
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 |
1128 | 1164 |
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
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 (3) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2020 | RCV000183317.26 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 20, 2023 | RCV000006347.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 9, 2023 | RCV000648847.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 15, 2022 | RCV002362566.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001836702.3 |
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
Help
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
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Peripheral neuropathy
Affected status: yes
Allele origin:
de novo
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV000927081.2
First in ClinVar: Jul 24, 2019 Last updated: Feb 20, 2022 |
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Pathogenic
(Jun 15, 2018)
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criteria provided, single submitter
Method: research
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Myofibrillar myopathy 6
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV000924465.1
First in ClinVar: Jun 23, 2019 Last updated: Jun 23, 2019 |
Comment:
The heterozygous p.Pro209Leu variant was identified by our study in one individual with myofibrillar myopathy. Trio exome analysis showed this variant to be de novo. … (more)
The heterozygous p.Pro209Leu variant was identified by our study in one individual with myofibrillar myopathy. Trio exome analysis showed this variant to be de novo. The p.Pro209Leu variant is pathogenic based off of our findings, multiple de novo reports in ClinVar, and the literature. (less)
Clinical Features:
Axonal sensorimotor polyneuropathy (present)
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Pathogenic
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Myofibrillar myopathy 6
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV000807268.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 11, 2022 |
Comment:
This mutation has been previously reported as disease-causing and was found once in our laboratory as a de novo change in a 4-year-old male with … (more)
This mutation has been previously reported as disease-causing and was found once in our laboratory as a de novo change in a 4-year-old male with muscular weakness, tight heel cords, restrictive cardiomyopathy. (less)
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Pathogenic
(Oct 01, 2020)
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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: SCV000235747.13
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23341456, 26545904, 21423662, 30105547, 29338979, 30384889, 27321750, 22734908, 25728519, 21898660, 21361913, 19085932, 28831623, 27443559, 30023292, 28224639, 30061062, 30145633, 29552495, 30499714, 30559338, 29405094, 25273835, 32472079, 32453099) (less)
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Pathogenic
(Dec 09, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000770668.6
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 209 of the BAG3 protein (p.Pro209Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 209 of the BAG3 protein (p.Pro209Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with myofibrillar myopathy (PMID: 19085932, 20605452, 21361913, 22734908, 25208129, 25728519, 26545904, 27443559). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 5981). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BAG3 protein function. Experimental studies have shown that this missense change affects BAG3 function (PMID: 19085932, 21898660, 25273835, 27321750, 27443559). This variant disrupts the p.Pro209 amino acid residue in BAG3. Other variant(s) that disrupt this residue have been observed in individuals with BAG3-related conditions (PMID: 25208129, 27164712), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 15, 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: SCV002656532.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.P209L pathogenic mutation (also known as c.626C>T), located in coding exon 3 of the BAG3 gene, results from a C to T substitution at … (more)
The p.P209L pathogenic mutation (also known as c.626C>T), located in coding exon 3 of the BAG3 gene, results from a C to T substitution at nucleotide position 626. The proline at codon 209 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in numerous individuals with myofibrillar myopathy and was found to be de novo in these individuals (Selcen D et al. Ann Neurol, 2009 Jan;65:83-9; Jaffer F et al. J Peripher Nerv Syst, 2012 Jun;17:210-6; Lee HC et al. Clin Genet, 2012 Apr;81:394-8; Kostera-Pruszczyk A et al. J Muscle Res Cell Motil, 2015 Dec;36:423-32; Konersman CG et al. Neuromuscul Disord, 2015 May;25:418-22; D'Avila F et al. J Muscle Res Cell Motil, 2016 06;37:101-15; Vasilescu C et al. J Am Coll Cardiol, 2018 11;72:2324-2338; Andersen AG et al. Neuromuscul Disord, 2018 09;28:798-801; Schänzer A et al. Mol Genet Metab, 2018 03;123:388-399; Kim SJ et al. Genes Genomics, 2018 12;40:1269-1277; Noury JB et al. Muscle Nerve, 2018 02;57:330-334; Herman I et al. Muscle Nerve, 2021 03;63:304-310; Zhan L et al. Medicine (Baltimore), 2022 Jan;101:e28484). In vivo studies showed this alteration impacts protein function (Kimura K et al. Nat Commun, 2021 06;12:3575). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(May 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Myofibrillar myopathy 6
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005329508.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The missense variant c.626C>T (p.Pro209Leu) in the BAG3 gene has been reported previously in heterozygous state in individuals affected with myofibrillar myopathy and cardiomyopathy. Experimental … (more)
The missense variant c.626C>T (p.Pro209Leu) in the BAG3 gene has been reported previously in heterozygous state in individuals affected with myofibrillar myopathy and cardiomyopathy. Experimental studies have shown that this missense change affects protein function (Kimura et al., 2021; D'Avila et al., 2016). This variant is absent in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic (Multiple submitters). The amino acid Proline at position 209 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Pro209Leu in BAG3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the musculoskeletal system (present)
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Pathogenic
(Feb 01, 2017)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246714.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 01, 2012)
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no assertion criteria provided
Method: literature only
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MYOPATHY, MYOFIBRILLAR, 6
Affected status: not provided
Allele origin:
unknown
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OMIM
Accession: SCV000026529.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 26, 2017 |
Comment on evidence:
In 3 unrelated patients with late-childhood onset of autosomal dominant myofibrillar myopathy-6 (MFM6; 612954), Selcen et al. (2009) identified a heterozygous 626C-T transition in exon … (more)
In 3 unrelated patients with late-childhood onset of autosomal dominant myofibrillar myopathy-6 (MFM6; 612954), Selcen et al. (2009) identified a heterozygous 626C-T transition in exon 3 of the BAG3, gene, resulting in a pro209-to-leu (P209L) substitution. The mutation was not present in 200 control individuals. Patients showed a rapidly progressive myopathy affecting both skeletal and cardiac muscle with severe respiratory insufficiency. In vitro functional expression studies showed that the mutant protein tended to aggregate into small granules, suggesting altered folding. Lee et al. (2012) identified a de novo heterozygous P209L mutation in a Chinese girl with onset of myofibrillar myopathy at age 6 years. She had slowly progressive muscle weakness, clumsy walking, rapidly progressive contractures of the Achilles tendons, limited spinal movement, mildly restrictive lung disease, hypertrophic cardiomyopathy, prolonged QT interval, and decreased motor nerve conduction velocities, suggesting a neurogenic axonal disease. Electron microscopy of muscle biopsy showed sarcoplasmic accumulations of electron-dense granulofilamentous material and myofibrillar degeneration with minicores. The patient and her father had an R258W missense mutation (603383.0009) in the BAG3 gene. Her father had no abnormal neuromuscular findings, but asymptomatic prolonged QT interval. It was unclear whether the R258W mutation contributed to the phenotype of either individual. In 4 patients from 3 unrelated families with MFM6, Odgerel et al. (2010) identified a heterozygous P209L mutation. The mutation occurred de novo in 2 patients. Two brothers inherited the mutation from their unaffected father, who was somatic mosaic for the mutation, with an expression level of 17% in the peripheral blood lymphocytes. In 4 patients with MFM6, Jaffer et al. (2012) identified a heterozygous P209L mutation. One of the patients had a sister who was similarly affected, but DNA was not available. Their father had died of a similar but milder disorder at age 30 years, suggesting that he may have been somatic mosaic for the mutation. (less)
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Pathogenic
(Jan 29, 2019)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
de novo
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Molecular Genetics laboratory, Necker Hospital
Accession: SCV004031322.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Clinical Features:
Myopathy (present)
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not provided
(-)
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no classification provided
Method: literature only
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Myofibrillar myopathy 6
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000055844.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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Ultrasound evaluation of diaphragm motion in BAG-3 myofibrillar myopathy: A case report. | Zhan L | Medicine | 2022 | PMID: 35029900 |
Overexpression of human BAG3(P209L) in mice causes restrictive cardiomyopathy. | Kimura K | Nature communications | 2021 | PMID: 34117258 |
Clinical exome sequencing in the diagnosis of pediatric neuromuscular disease. | Herman I | Muscle & nerve | 2021 | PMID: 33146414 |
Genetic Basis of Severe Childhood-Onset Cardiomyopathies. | Vasilescu C | Journal of the American College of Cardiology | 2018 | PMID: 30384889 |
BAG3 mutation in a patient with atypical phenotypes of myofibrillar myopathy and Charcot-Marie-Tooth disease. | Kim SJ | Genes & genomics | 2018 | PMID: 30145633 |
BAG3 myopathy is not always associated with cardiomyopathy. | Andersen AG | Neuromuscular disorders : NMD | 2018 | PMID: 30061062 |
Dysregulated autophagy in restrictive cardiomyopathy due to Pro209Leu mutation in BAG3. | Schänzer A | Molecular genetics and metabolism | 2018 | PMID: 29338979 |
Rigid spine syndrome associated with sensory-motor axonal neuropathy resembling Charcot-Marie-Tooth disease is characteristic of Bcl-2-associated athanogene-3 gene mutations even without cardiac involvement. | Noury JB | Muscle & nerve | 2018 | PMID: 28224639 |
Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy. | D'Avila F | Journal of muscle research and cell motility | 2016 | PMID: 27443559 |
Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling. | Quintana MT | The American journal of pathology | 2016 | PMID: 27321750 |
Target-enrichment sequencing and copy number evaluation in inherited polyneuropathy. | Wang W | Neurology | 2016 | PMID: 27164712 |
BAG3-related myopathy, polyneuropathy and cardiomyopathy with long QT syndrome. | Kostera-Pruszczyk A | Journal of muscle research and cell motility | 2015 | PMID: 26545904 |
BAG3 myofibrillar myopathy presenting with cardiomyopathy. | Konersman CG | Neuromuscular disorders : NMD | 2015 | PMID: 25728519 |
Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency. | Ruparelia AA | Acta neuropathologica | 2014 | PMID: 25273835 |
Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies. | Semmler AL | Orphanet journal of rare diseases | 2014 | PMID: 25208129 |
BAG3 mutations: another cause of giant axonal neuropathy. | Jaffer F | Journal of the peripheral nervous system : JPNS | 2012 | PMID: 22734908 |
BAG3-related myofibrillar myopathy in a Chinese family. | Lee HC | Clinical genetics | 2012 | PMID: 21361913 |
Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2012 | PMID: 20301672 |
Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes. | Arimura T | Human mutation | 2011 | PMID: 21898660 |
Clinical and myopathological evaluation of early- and late-onset subtypes of myofibrillar myopathy. | Olivé M | Neuromuscular disorders : NMD | 2011 | PMID: 21676617 |
Inheritance patterns and phenotypic features of myofibrillar myopathy associated with a BAG3 mutation. | Odgerel Z | Neuromuscular disorders : NMD | 2010 | PMID: 20605452 |
Mutation in BAG3 causes severe dominant childhood muscular dystrophy. | Selcen D | Annals of neurology | 2009 | PMID: 19085932 |
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Text-mined citations for rs121918312 ...
HelpRecord last updated Oct 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.