rs397516881
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_004281.4(BAG3):c.1363G>A(p.Glu455Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E455E) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
BAG3
NM_004281.4 missense
NM_004281.4 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 9.48
Genes affected
BAG3 (HGNC:939): (BAG cochaperone 3) BAG proteins compete with Hip for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The protein encoded by this gene contains a WW domain in the N-terminal region and a BAG domain in the C-terminal region. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.937
PP5
?
Variant 10-119676917-G-A is Pathogenic according to our data. Variant chr10-119676917-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 44778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BAG3 | NM_004281.4 | c.1363G>A | p.Glu455Lys | missense_variant | 4/4 | ENST00000369085.8 | |
BAG3 | XM_005270287.2 | c.1360G>A | p.Glu454Lys | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BAG3 | ENST00000369085.8 | c.1363G>A | p.Glu455Lys | missense_variant | 4/4 | 1 | NM_004281.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Feb 21, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2021 | 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) - |
Myofibrillar myopathy 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | 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. - |
Primary dilated cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 07, 2017 | 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. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 26, 2020 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of methylation at E455 (P = 0.0138);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at