rs1554877224

Positions:

• chr10-119672353-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004281.4(BAG3):​c.607dup​(p.Arg203ProfsTer52) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P202P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BAG3 NM_004281.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.13

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-119672353-G-GC is Pathogenic according to our data. Variant chr10-119672353-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 410229.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.607dup	p.Arg203ProfsTer52	frameshift_variant	3/4	ENST00000369085.8
BAG3	XM_005270287.2	c.607dup	p.Arg203ProfsTer52	frameshift_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8	c.607dup	p.Arg203ProfsTer52	frameshift_variant	3/4	1	NM_004281.4	P1
BAG3	ENST00000450186.1	c.433dup	p.Arg145ProfsTer52	frameshift_variant	4/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 410229). This variant has not been reported in the literature in individuals affected with BAG3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg203Profs*52) in the BAG3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BAG3 are known to be pathogenic (PMID: 21353195, 25008357). -

Dilated cardiomyopathy 1HH Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2016

This sequence change inserts 1 nucleotide in exon 3 of the BAG3 mRNA (c.607dupC), causing a frameshift at codon 203. This creates a premature translational stop signal (p.Arg203Profs*52) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in BAG3 are known to be pathogenic (PMID: 21353195, 25008357). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2021

The c.607dupC variant, located in coding exon 3 of the BAG3 gene, results from a duplication of C at nucleotide position 607, causing a translational frameshift with a predicted alternate stop codon (p.R203Pfs*52). This alteration has not been previously reported; however, loss of function alterations have been reported in numerous cases of familial dilated cardiomyopathy, including many families with strong segregation with disease (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; Chami N et al. Can J Cardiol. 2014;30(12):1655-61; Feldman AM et al. J Cell Physiol. 2014;229(11):1697-702; Franaszczyk M et al. J Transl Med. 2014;12:192; van Spaendonck-Zwarts KY et al. Eur Heart J. 2014;35(32):2165-73). In addition, in Norton et al. 2011, BAG3 knockdown in a zebrafish model showed heart failure with decreased fractional shortening and pericardial effusion. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554877224; hg19: chr10-121431865;