NM_004281.4(BAG3):c.1067dup (p.Pro357fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 23, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003807770.2

Allele description [Variation Report for NM_004281.4(BAG3):c.1067dup (p.Pro357fs)]

NM_004281.4(BAG3):c.1067dup (p.Pro357fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

10q26.11

Genomic location:

Preferred name:

NM_004281.4(BAG3):c.1067dup (p.Pro357fs)

HGVS:

NC_000010.11:g.119676621dup
NG_016125.1:g.30252dup
NM_004281.4:c.1067dupMANE SELECT
NP_004272.2:p.Pro357Thrfs
NP_004272.2:p.Pro357fs
LRG_742t1:c.1067dup
LRG_742:g.30252dup
LRG_742p1:p.Pro357Thrfs
NC_000010.10:g.121436128_121436129insC
NC_000010.10:g.121436133dup
NM_004281.3:c.1067dup

Protein change:

P357fs

Molecular consequence:

NM_004281.4:c.1067dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV004591992	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 23, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28436997, 32160020, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004591992

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 23, 2022)

germline

clinical testing

PubMed (3)
[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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Truncating mutations on myofibrillar myopathies causing genes as prevalent molecular explanations on patients with dilated cardiomyopathy.

Janin A, N'Guyen K, Habib G, Dauphin C, Chanavat V, Bouvagnet P, Eschalier R, Streichenberger N, Chevalier P, Millat G.

Clin Genet. 2017 Dec;92(6):616-623. doi: 10.1111/cge.13043. Epub 2017 May 18.

PubMed [citation]

PMID:: 28436997

Variant Interpretation for Dilated Cardiomyopathy: Refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study.

Morales A, Kinnamon DD, Jordan E, Platt J, Vatta M, Dorschner MO, Starkey CA, Mead JO, Ai T, Burke W, Gastier-Foster J, Jarvik GP, Rehm HL, Nickerson DA, Hershberger RE; DCM Precision Medicine study of the DCM Consortium.; DCM Consortium institutions and personnel participating in this study: Study Principal Investigator and Co-Investigators,DCM Consortium Clinical Site Principal Investigators and Clinical Site Other Significant Contributors (OSC). The following clinical sites and individuals contributed to the submission of RO 1 H L 128857 as Site Principal Investigators (Site Pl) or as Other Significant Contributors (OSC),Dr. Huggins also served as study co-principal investigator,The following clinical site was added following approval of NHGRI supplemental funding but prior to initiation of enrollment,The following clinical sites were added following study activation..

Circ Genom Precis Med. 2020 Apr;13(2):e002480. doi: 10.1161/CIRCGEN.119.002480. Epub 2020 Mar 11.

PubMed [citation]

PMID:: 32160020
PMCID:: PMC8070981

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004591992.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BAG3 protein in which other variant(s) (p.Arg473*) have been determined to be pathogenic (PMID: 28436997, 32160020). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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.Pro357Thrfs*4) in the BAG3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 219 amino acid(s) of the BAG3 protein.

#	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: Sep 29, 2024

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