NM_004281.4(BAG3):c.77G>A (p.Trp26Ter) AND multiple conditions

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 29, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002483674.2

Allele description [Variation Report for NM_004281.4(BAG3):c.77G>A (p.Trp26Ter)]

NM_004281.4(BAG3):c.77G>A (p.Trp26Ter)

Gene:

BAG3:BAG cochaperone 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q26.11

Genomic location:

Preferred name:

NM_004281.4(BAG3):c.77G>A (p.Trp26Ter)

HGVS:

NC_000010.11:g.119651752G>A
NG_016125.1:g.5383G>A
NM_004281.4:c.77G>AMANE SELECT
NP_004272.2:p.Trp26Ter
NP_004272.2:p.Trp26Ter
LRG_742t1:c.77G>A
LRG_742:g.5383G>A
LRG_742p1:p.Trp26Ter
NC_000010.10:g.121411264G>A
NM_004281.3:c.77G>A
p.Trp26X

Protein change:

W26*

Links:

dbSNP: rs1554875409

NCBI 1000 Genomes Browser:

rs1554875409

Molecular consequence:

NM_004281.4:c.77G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Myofibrillar myopathy 6
Synonyms:: Myofibrillar myopathy, BAG3-related
Identifiers:: MONDO: MONDO:0013061; MedGen: C2751831; Orphanet: 199340; OMIM: 612954

Name:: Dilated cardiomyopathy 1HH (CMD1HH)
Identifiers:: MONDO: MONDO:0013479; MedGen: C3151293; Orphanet: 154; OMIM: 613881

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002784157	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 29, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004569715	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 29, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21353195, 25008357, 28436997, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002784157

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 29, 2021)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004569715

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 29, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy.

Norton N, Li D, Rieder MJ, Siegfried JD, Rampersaud E, Züchner S, Mangos S, Gonzalez-Quintana J, Wang L, McGee S, Reiser J, Martin E, Nickerson DA, Hershberger RE.

Am J Hum Genet. 2011 Mar 11;88(3):273-82. doi: 10.1016/j.ajhg.2011.01.016. Epub 2011 Feb 25.

PubMed [citation]

PMID:: 21353195
PMCID:: PMC3059419

See all PubMed Citations (5)

Details of each submission

From Fulgent Genetics, Fulgent Genetics, SCV002784157.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV004569715.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Trp26*) 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). 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: 28436997). ClinVar contains an entry for this variant (Variation ID: 505229). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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