ClinVar Miner

Submissions for variant NM_004281.4(BAG3):c.280A>T (p.Ile94Phe) (rs145393807)

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Total submissions: 12
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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, Partners HealthCare 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,; 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000154684 SCV000227328 likely benign not specified 2015-02-16 criteria provided, single submitter clinical testing
GeneDx RCV000154684 SCV000235744 likely benign not specified 2017-07-24 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.
Invitae RCV001085873 SCV000261250 likely benign Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2019-12-31 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics 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 Inc 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 Other strong data supporting benign classification
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, BAG3-related 2019-05-28 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 (, 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.

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