NM_004281.4(BAG3):c.280A>T (p.Ile94Phe) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Oct 1, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000154684.21

Allele description [Variation Report for NM_004281.4(BAG3):c.280A>T (p.Ile94Phe)]

NM_004281.4(BAG3):c.280A>T (p.Ile94Phe)

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.280A>T (p.Ile94Phe)

Other names:

p.I94F:ATT>TTT

HGVS:

NC_000010.11:g.119669950A>T
NG_016125.1:g.23581A>T
NM_004281.4:c.280A>TMANE SELECT
NP_004272.2:p.Ile94Phe
NP_004272.2:p.Ile94Phe
LRG_742t1:c.280A>T
LRG_742:g.23581A>T
LRG_742p1:p.Ile94Phe
NC_000010.10:g.121429462A>T
NM_004281.3:c.280A>T
O95817:p.Ile94Phe

Protein change:

I94F

Links:

UniProtKB: O95817#VAR_066778; dbSNP: rs145393807

NCBI 1000 Genomes Browser:

rs145393807

Molecular consequence:

NM_004281.4:c.280A>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000204362	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Apr 14, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21353195, 21459883, 24033266
SCV000227328	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely benign (Feb 16, 2015)	germline	clinical testing	Citation Link,
SCV000310055	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000612483	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Benign (May 5, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21353195, 21459883, 27042682, 27896284, 26467025
SCV004121736	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Oct 1, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	2	2	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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

See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000204362.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

Description

Variant classified as Uncertain Significance - Favor Benign. The p.Ile94Phe vari ant in BAG3 has been identified in 0.1% (89/66712) of European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs14 5393807). It has been reported in 2 individuals with DCM, though it reportedly d id not segregate with disease in 1 affected relative (Norton 2011, Villard 2011) . This variant has also been identified by our laboratory in one individual with reduced ejection fraction, hypokinesis and LBBB. Computational prediction tools and conservation analysis do not provide strong support for or against an impac t to the protein. In summary, while the clinical significance of the p.Ile94Phe variant is uncertain, its frequency and lack of segregation with disease suggest s that it is more likely to be benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

From Eurofins Ntd Llc (ga), SCV000227328.5

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

#	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		1	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV000310055.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV000612483.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004121736.1

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

#	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: Oct 20, 2024

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