NM_004281.4(BAG3):c.230C>T (p.Pro77Leu) AND not specified

Germline classification:: Benign/Likely benign (3 submissions)
Last evaluated:: Sep 18, 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:: RCV000150175.8

Allele description [Variation Report for NM_004281.4(BAG3):c.230C>T (p.Pro77Leu)]

NM_004281.4(BAG3):c.230C>T (p.Pro77Leu)

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.230C>T (p.Pro77Leu)

HGVS:

NC_000010.11:g.119669900C>T
NG_016125.1:g.23531C>T
NM_004281.4:c.230C>TMANE SELECT
NP_004272.2:p.Pro77Leu
NP_004272.2:p.Pro77Leu
LRG_742t1:c.230C>T
LRG_742:g.23531C>T
LRG_742p1:p.Pro77Leu
NC_000010.10:g.121429412C>T
NM_004281.3:c.230C>T
O95817:p.Pro77Leu

Protein change:

P77L

Links:

UniProtKB: O95817#VAR_066777; dbSNP: rs141355480

NCBI 1000 Genomes Browser:

rs141355480

Molecular consequence:

NM_004281.4:c.230C>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
SCV000197085	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Jun 5, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000612482	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Benign (Feb 24, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27042682, 26467025
SCV004099953	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Sep 18, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000197085

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Jun 5, 2014)

germline

clinical testing

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

SCV000612482

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Benign
(Feb 24, 2017)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004099953

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Sep 18, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	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

Progressive multifocal leukoencephalopathy in an immunocompetent patient.

van der Kolk NM, Arts P, van Uden IW, Hoischen A, van de Veerdonk FL, Netea MG, de Jong BA.

Ann Clin Transl Neurol. 2016 Mar;3(3):226-32. doi: 10.1002/acn3.279.

PubMed [citation]

PMID:: 27042682
PMCID:: PMC4774259

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000197085.4

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

Description

Pro77Leu in exon 2 of BAG3: This variant is not expected to have clinical signif icance due to a lack of conservation across species, including mammals. Of note, >45 mammals and other species have a leucine (Leu) at this position despite hig h nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has also been identi fied in 5/8600 European American chromosomes by the NHLBI Exome Sequencing Proje ct (http://evs.gs.washington.edu/EVS/; dbSNP rs141355480).

#	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		1	not provided	1	not provided

From Athena Diagnostics, SCV000612482.1

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

#	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, SCV004099953.1

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

Description

Variant summary: BAG3 c.230C>T (p.Pro77Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 251396 control chromosomes, predominantly at a frequency of 0.00047 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12-fold of the estimated maximal expected allele frequency for a pathogenic variant in BAG3 causing Dilated Cardiomyopathy phenotype (3.9e-05), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.230C>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

#	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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