Submissions for variant NM_004281.3(BAG3):c.772C>T (p.Arg258Trp)

gnomAD frequency: 0.00036  dbSNP: rs117671123

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000037897	SCV000054734	benign	not specified	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037897	SCV000061559	benign	not specified	2015-03-18	criteria provided, single submitter	clinical testing	p.Arg258Trp in exon 3 of BAG3: This variant is not expected to have clinical sig nificance because it has been identified in 1.6% (135/8628) of East Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs117671123).
GeneDx	RCV000037897	SCV000235738	benign	not specified	2017-02-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490529	SCV000267220	benign	Myofibrillar myopathy 6	2016-03-18	criteria provided, single submitter	reference population
Invitae	RCV001081302	SCV000288309	benign	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-01-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000490529	SCV000360582	benign	Myofibrillar myopathy 6	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590218	SCV000698282	benign	not provided	2017-08-02	criteria provided, single submitter	clinical testing	Variant summary: The BAG3 c.772C>T (p.Arg258Trp) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 141/120824 control chromosomes (1 homozygote) from ExAC, predominantly observed in the East Asian subpopulation at a frequency of 0.015647 (135/8628). This frequency is about 401 times the estimated maximal expected allele frequency of a pathogenic BAG3 variant (0.0000391), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant has been found in one patient with patient with restrictive lung disease, a rapidly progressive proximal myopathy, rigid spine, bilateral Achilles tendon tightening, hypertrophic cardiomyopathy with restrictive physiology and a prolonged QT interval (Lee_2012). The patient also carried a de novo variant c.626C>T (p.Pro209Leu) which is regarded to explain the cardiac disease in the patient. In addition, father who was incidentally found to have prolonged QT interval also carried the variant of interest p.Arg258Trp. Thus the variant of interest may be a functional polymorphism. Multiple clinical diagnostic laboratories in ClinVar classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Ambry Genetics	RCV000618102	SCV000736150	benign	Cardiovascular phenotype	2017-12-07	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590218	SCV000885058	benign	not provided	2018-02-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000490529	SCV001138176	benign	Myofibrillar myopathy 6	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001107316	SCV001264457	likely benign	Dilated cardiomyopathy 1HH	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Fulgent Genetics, Fulgent Genetics	RCV001081302	SCV002801977	benign	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2021-08-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486548	SCV004239758	benign	Cardiomyopathy	2022-11-11	criteria provided, single submitter	clinical testing
OMIM	RCV000032662	SCV000056425	uncertain significance	Myofibrillar myopathy	2012-04-01	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000037897	SCV001917138	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590218	SCV001956933	likely benign	not provided		no assertion criteria provided	clinical testing