ClinVar Genomic variation as it relates to human health
NM_004281.4(BAG3):c.892G>A (p.Val298Met)
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(6); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004281.4(BAG3):c.892G>A (p.Val298Met)
Variation ID: 196379 Accession: VCV000196379.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q26.11 10: 119672639 (GRCh38) [ NCBI UCSC ] 10: 121432151 (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 Jun 29, 2015 Aug 4, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004281.4:c.892G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004272.2:p.Val298Met missense NC_000010.11:g.119672639G>A NC_000010.10:g.121432151G>A NG_016125.1:g.26270G>A LRG_742:g.26270G>A LRG_742t1:c.892G>A LRG_742p1:p.Val298Met - Protein change
- V298M
- Other names
- p.Val298Met
- Canonical SPDI
- NC_000010.11:119672638: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.
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
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 |
1121 | 1157 |
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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Mar 1, 2024 | RCV000177195.21 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 11, 2023 | RCV000249859.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 25, 2022 | RCV000233577.9 |
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
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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Uncertain significance
(Jul 27, 2021)
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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: SCV002785552.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1HH
Myofibrillar myopathy 6
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000288312.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 298 of the BAG3 protein (p.Val298Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 298 of the BAG3 protein (p.Val298Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 28798025). ClinVar contains an entry for this variant (Variation ID: 196379). 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 not expected to disrupt BAG3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(May 31, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225335.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Number of individuals with the variant: 2
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Uncertain significance
(Jul 17, 2023)
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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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Revvity Omics, Revvity
Accession: SCV003829750.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 11, 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: SCV000320190.8
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
The p.V298M variant (also known as c.892G>A), located in coding exon 3 of the BAG3 gene, results from a G to A substitution at nucleotide … (more)
The p.V298M variant (also known as c.892G>A), located in coding exon 3 of the BAG3 gene, results from a G to A substitution at nucleotide position 892. The valine at codon 298 is replaced by methionine, an amino acid with highly similar properties. This variant was reported in the control population in a study of subjects with dilated cardiomyopathy, and has been detected in a family with left ventricular non-compaction cardiomyopathy who also had variants in other cardiac-related genes (Norton N et al. Am J Hum Genet. 2011 Mar; 88(3):273-82; Miszalski-Jamka K. Circ Cardiovasc Genet. 2017 Aug;10(4)). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (less)
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Uncertain significance
(Jan 20, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000229031.5
First in ClinVar: Jun 29, 2015 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 1
Sex: mixed
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Likely benign
(Mar 01, 2024)
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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: SCV003916647.11
First in ClinVar: Apr 23, 2023 Last updated: Aug 04, 2024 |
Comment:
BAG3: BP4
Number of individuals with the variant: 2
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550763.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BAG3 p.Val298Met variant was identified in the literature in two patients with left ventricular hypertrabeculation but was also found in a healthy control (Miszalski-Jamka_2018_PMID:28798025; … (more)
The BAG3 p.Val298Met variant was identified in the literature in two patients with left ventricular hypertrabeculation but was also found in a healthy control (Miszalski-Jamka_2018_PMID:28798025; Norton_2011_PMID:21353195). The variant was identified in dbSNP (ID: rs150048651), LOVD 3.0 and ClinVar (classified as uncertain significance by Ambry Genetics, EGL Genetic Diagnostics, and Invitae). The variant was identified in control databases in 22 of 281356 chromosomes at a frequency of 0.00007819 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 20 of 128474 chromosomes (freq: 0.000156), Other in 1 of 7204 chromosomes (freq: 0.000139) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Val298 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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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Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction. | Miszalski-Jamka K | Circulation. Cardiovascular genetics | 2017 | PMID: 28798025 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BAG3 | - | - | - | - |
Text-mined citations for rs150048651 ...
HelpRecord last updated Aug 04, 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.