Submissions for variant NM_004281.4(BAG3):c.211C>T (p.Arg71Trp)

gnomAD frequency: 0.00008  dbSNP: rs387906874

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456156	SCV000550833	likely benign	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2025-01-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000456156	SCV000894521	uncertain significance	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2018-10-31	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852638	SCV000995343	likely benign	Primary dilated cardiomyopathy	2019-05-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811196	SCV002048838	uncertain significance	not provided	2020-10-25	criteria provided, single submitter	clinical testing	The BAG3 c.211C>T; p.Arg71Trp variant (rs387906874) is reported in the literature in several individuals affected with cardiomyopathy (Norton 2011, Cowan 2018, van Lint 2019). This variant is also reported in ClinVar (Variation ID: 30396). This variant is found in the Finnish European population with an allele frequency of 0.07% (17/25104 alleles) in the Genome Aggregation Database. The arginine at codon 71 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.37). Due to limited information, the clinical significance of the p.Arg71Trp variant is uncertain at this time. Pathogenic variants in BAG3 are associated with autosomal dominant dilated cardiomyopathy 1HH (MIM: 613881) and myofibrillar myopathy 6 (MIM: 612954). References: Norton et al. Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am J Hum Genet. 2011 Mar 11;88(3):273-82. Cowan et al. Multigenic Disease and Bilineal Inheritance in Dilated Cardiomyopathy Is Illustrated in Nonsegregating LMNA Pedigrees. Circ Genom Precis Med. 2018 Jul;11(7):e002038. van Lint et al. Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. Neth Heart J. 2019 Jun;27(6):304-309.
Ambry Genetics	RCV002415426	SCV002725290	likely benign	Cardiovascular phenotype	2023-05-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003234916	SCV003933745	likely benign	not specified	2023-05-16	criteria provided, single submitter	clinical testing	Variant summary: BAG3 c.211C>T (p.Arg71Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251304 control chromosomes (gnomAD). The observed variant frequency is approximately 4-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 benign. c.211C>T has been reported in the literature in two individuals affected with Dilated Cardiomyopathy from the same family, however both also shared variants in other cardiac-related genes (Norton_2011, Cowan_2018). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. The variant has also been reported in an individual with an unknown/unspecified cardiomyopathy who had a co-occurring pathogenic variant in MYBPC3 (c.1505G>A, p.Arg502Gln), providing supporting evidence for a benign role (van Lint_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30012837, 21353195, 30847666). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=3) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Lildballe Lab, Aarhus University Hospital	RCV000852638	SCV005200550	uncertain significance	Primary dilated cardiomyopathy	2024-03-01	criteria provided, single submitter	research	PM2(s), BP6(sup)
OMIM	RCV000023349	SCV000044640	pathogenic	Dilated cardiomyopathy 1HH	2011-03-11	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000852638	SCV001434726	uncertain significance	Primary dilated cardiomyopathy		no assertion criteria provided	research