Description
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.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
