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

gnomAD frequency: 0.00085  dbSNP: rs145393807

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172519	SCV000051368	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154684	SCV000204362	uncertain significance	not specified	2016-04-14	criteria provided, single submitter	clinical testing	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.
Eurofins Ntd Llc (ga)	RCV000154684	SCV000227328	likely benign	not specified	2015-02-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000172519	SCV000235744	benign	not provided	2020-01-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21353195, 21459883, 27042682, 27896284, 23861362, 26350513, 26886200, 28798025)
Invitae	RCV001085873	SCV000261250	likely benign	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000154684	SCV000310055	likely benign	not specified		criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000172519	SCV000610129	likely benign	not provided	2017-04-12	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000154684	SCV000612483	benign	not specified	2017-05-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622150	SCV000735531	likely benign	Cardiovascular phenotype	2019-03-19	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.
Klaassen Lab, Charite University Medicine Berlin	RCV000853125	SCV000995836	uncertain significance	Primary dilated cardiomyopathy	2019-07-03	criteria provided, single submitter	research
Mendelics	RCV000988454	SCV001138175	benign	Myofibrillar myopathy 6	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172519	SCV004033074	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BAG3: BS1, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154684	SCV004121736	likely benign	not specified	2023-10-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172519	SCV004563304	likely benign	not provided	2023-05-30	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000172519	SCV000924761	uncertain significance	not provided	2015-09-17	no assertion criteria provided	provider interpretation	The patient had genetic testing with a comprehensive cardiomyopathy panel. The test included 77 genes associated with various hereditary cardiomyopathies: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3, BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL, NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43,TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. Analysis included both sequencing and array-based comparative genome hybridization to look for duplications and deletions (excluding mitochondrial genes, FKTN, GATAD1) Results showed that a variant was found: -p.Ile94Phe (c.280 A>T in the BAG3 gene. This variant is reviewed in detail below. The lab classifies this variant as a variant of unknown significance. Given a lack of case data, lack of segregation and presence in the general population we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least two unrelated cases of DCM in the literature (not including this patient's family). In one family this variant failed to segregate with disease. Villard E et al., 2011 reported finding this variant in one individual with familial DCM, but failed to segregate in an affected individual and was thereby excluded as a disease causing variant. Norton N et al., 2011 also reported this variant in one individual with DCM but was reported as a variant because of its presence in controls. The Laboratory for Molecular Medicine has seen this in one individual and classifies this as a a variant of uncertain significance. Emory Genetics, the Biesecker Lab classify this as likely benign. In silico analysis with PolyPhen-2 predicts the variant to be damaging (HumVar: 0.975). The Ile at codon 94 is conserved across species, as are neighboring amino acids. Other variants have not been reported in association with disease at this codon (94) and nearby codons. There is substantial variation at codon 94 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 17, 2015). This is a population frequency of 1/682 people in the cohort. 91 of those individuals were European with a frequency of 1/400 caucasian individuals.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172519	SCV001798256	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172519	SCV001923848	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172519	SCV001930676	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172519	SCV001955786	likely benign	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172519	SCV001963327	likely benign	not provided		no assertion criteria provided	clinical testing