ClinVar Genomic variation as it relates to human health

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.

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.

This variant is associated with the following publications: (PMID: 21353195, 21459883, 27042682, 27896284, 23861362, 26350513, 26886200, 28798025)

BAG3: BS1, BS2

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.