10-119672373-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_004281.4(BAG3):c.626C>T(p.Pro209Leu) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P209A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

BAG3
NM_004281.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 6.13

Publications

103 publications found

Variant links:

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]

BAG3 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1HH
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
myofibrillar myopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, ClinGen
myofibrillar myopathy 6
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-tooth disease, axonal, type 2JJ
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
distal hereditary motor neuropathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BAG3 links:

ENSG00000295480 (HGNC:):

ENSG00000295480 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-119672372-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1369248.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

PP5

Variant 10-119672373-C-T is Pathogenic according to our data. Variant chr10-119672373-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4 link	c.626C>T	p.Pro209Leu	missense_variant	Exon 3 of 4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2 link	c.626C>T	p.Pro209Leu	missense_variant	Exon 3 of 4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8 link	c.626C>T	p.Pro209Leu	missense_variant	Exon 3 of 4	1	NM_004281.4	ENSP00000358081.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000498

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Myofibrillar myopathy 6

Pathogenic:4Other:1

Jun 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 01, 2017

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jun 15, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

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. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Pathogenic:3

Jan 29, 2019

Molecular Genetics laboratory, Necker Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 01, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Feb 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peripheral neuropathy

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH

Pathogenic:1

Apr 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Cardiovascular phenotype

Pathogenic:1

Aug 15, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;T

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.072

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

6.1

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.96

MutPred

0.84

Gain of sheet (P = 0.0266);.;

MVP

0.99

MPC

0.42

ClinPred

1.0

GERP RS

6.2

Varity_R

0.71

gMVP

0.65

Mutation Taster

=20/80

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over