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

gnomAD frequency: 0.00033  dbSNP: rs141355480

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150175	SCV000197085	likely benign	not specified	2014-06-05	criteria provided, single submitter	clinical testing	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).
GeneDx	RCV001090931	SCV000517070	likely benign	not provided	2020-12-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27042682)
Invitae	RCV000472056	SCV000550829	likely benign	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000150175	SCV000612482	benign	not specified	2017-02-24	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852639	SCV000995344	likely benign	Cardiomyopathy	2019-04-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001090931	SCV001246713	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	BAG3: BP4, BS2
Ambry Genetics	RCV002444612	SCV002734285	likely benign	Cardiovascular phenotype	2019-08-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000852639	SCV003837857	likely benign	Cardiomyopathy	2022-03-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150175	SCV004099953	benign	not specified	2023-09-18	criteria provided, single submitter	clinical testing	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001090931	SCV001743599	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001090931	SCV001924252	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001090931	SCV001930648	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001090931	SCV001955704	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001090931	SCV001970630	likely benign	not provided		no assertion criteria provided	clinical testing