10-119676479-C-T

Position:

• chr10-119676479-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000369085.8(BAG3):​c.925C>T​(p.Arg309Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BAG3 ENST00000369085.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.49

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 31 pathogenic variants in the truncated region.
• PP5: Variant 10-119676479-C-T is Pathogenic according to our data. Variant chr10-119676479-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 228322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG3	NM_004281.4	c.925C>T	p.Arg309Ter	stop_gained	4/4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.922C>T	p.Arg308Ter	stop_gained	4/4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.925C>T	p.Arg309Ter	stop_gained	4/4	1	NM_004281.4	ENSP00000358081	P1
BAG3	ENST00000450186.1	c.748C>T	p.Arg250Ter	stop_gained	5/5	5		ENSP00000410036

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461846 Hom.: 0 Cov.: 72 AF XY: 0.00000413 AC XY: 3 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	This sequence change creates a premature translational stop signal (p.Arg309*) in the BAG3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 267 amino acid(s) of the BAG3 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25448463). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228322). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2021	Reported in association with dilated cardiomyopathy (Villard et al., 2011; Chami et al., 2014; Dominguez et al., 2018; Augusto et al., 2019; Gigli et al., 2019; Seidel et al., 2021); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 267 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 228322; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30442290, 31514951, 21459883, 25448463, 34213952, 31317183, 20001957, 28211974) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 23, 2021	- -

Primary familial dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Apr 26, 2016

- -

Primary dilated cardiomyopathy;C0027059:Myocarditis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Klaassen Lab, Charite University Medicine Berlin

-

- -

Primary dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 24, 2015

The p.Arg309X variant in BAG3 has been previously reported in 5 individuals with DCM (Villard 2011, Chami 2014, LMM unpublished data) and segregated with the di sease in greater than 15 affected family members (Chami 2014). It was absent fro m large population studies. This nonsense variant leads to a premature terminati on codon at position 309. Based on its position (last exon), it is predicted to result in a truncated protein rather than case loss of function. In summary, th is variant meets our criteria to be classified as pathogenic for DCM in an autos omal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based up on segregation studies and absence from controls. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2022

The p.R309* pathogenic mutation (also known as c.925C>T), located in coding exon 4 of the BAG3 gene, results from a C to T substitution at nucleotide position 925. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration occurs at the 3' terminus of theBAG3 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 46% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). In one study, this alteration segregated with disease in three families with dilated cardiomyopathy (DCM) and in another study, it was detected in one individual with DCM (Chami N et al. Can J Cardiol, 2014 Dec;30:1655-61; Villard E et al. Eur. Heart J., 2011 May;32:1065-76). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

BAG3-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2024

The BAG3 c.925C>T variant is predicted to result in premature protein termination (p.Arg309*). This variant has been reported in numerous individuals with dilated cardiomyopathy and found to segregate with the disorder in multiple families (Villard et al. 2011. PubMed ID: 21459883; Chami et al. 2014. PubMed ID: 25448463; Online Table 1, Gigli et al. 2019. PubMed ID: 31514951; Seidel et al. 2021. PubMed ID: 34213952). This variant has not been reported in a large population database, indicating this variant is rare. This variant resides in the terminal exon and downstream loss-of-function variants are well documented to be causative for dilated cardiomyopathy (Villard et al. 2011. PubMed ID: 21459883; Dominguez et al. 2018. PubMed ID: 30442290). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	D
Vest4		0.92
GERP RS		5.0

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

LitVar

Other links and lift over

dbSNP: rs869248137; hg19: chr10-121435991;