ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.133C>T (p.Arg45Cys) (rs747820097)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000469809 SCV000550846 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2016-04-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 45 of the BAG3 protein (p.Arg45Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs747820097, ExAC 0.01%) but has not been reported in the literature in individuals with a BAG3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786109 SCV000924758 uncertain significance not provided 2017-04-29 no assertion criteria provided provider interpretation Given the absence of this variant in case reports, an uncertain association between missense change and disease, and its low frequency in general population databases, we classify this variant as a variant of uncertain significance. The BAG3 gene belongs to a family of co-chaperones that play a role in anti-apoptosis. BAG3 localizes within the Z-disc and is thought to act as a signaling molecule. Ray Hershberger's group reported BAG3 variants in patients with DCM (Norton et al 2011). In one kindred they performed exome sequencing and copy number variant analysis and identified an 8.7 kbp deletion in BAG3 that was present in all 7 affected family members and absent in 355 controls. They then sequenced exons 2, 3, and 4 in 311 probands with DCM (who had normal sequencing of 15 other DCM genes) and found heterozygous point variants in 7 unrelated probands. This included one frameshift and two nonsense variants. So in their sample, 3/311 cases had a rare nonsense or frameshift. In contrast, 3/~60,000 individuals in ExAC have a nonsense or frameshift variant in BAG3. Segregation data was available for one nonsense variant, which was present in all four affected family members (three siblings and a parent). A knockdown of zebrafish recapitulated the cardiomyopathy and heart failure phenotype. They noted a wide age of onset (21 to 64yo) and varied severity. Arimura et al (2011) analyzed BAG3 in 72 Japanese probands and found missense variants in 2 cases. Chami et al (2014) performed exome sequencing on 44 individuals from families with DCM (unclear if 44 probands or mix of probands and relatives). They found two truncating variants in four families with a LOD score across three families of 3.8. Franaszczyk et al (2014) analyzed BAG3 by qtPCR and sequencing in 90 unrelated DCM patients from Poland. They found rare variants in 6/90 families including three nonsense or frameshift variants and a 17,990 bp deletion removing exons 3-4. These variants segregated with disease in 1-3 additional affected family members in each pedigree. They also noted a slightly later onset and overall lower penetrance in truncating vs. non-truncating variants. All nonsense and frameshift BAG3 variants in ClinVar are classified as likely pathogenic or pathogenic, with submissions from LMM, GeneDx, and Blueprint. In contrast, nearly all of the 44 missense variants in ClinVar submitted by clinical labs are classified as variants of uncertain significance or (likely) benign. There is one likely pathogenic classification for one of the missense variants reported by Norton et al (2011). The data in ClinVar aligns with data from ExAC, which indicates that BAG3 is tolerant of missense change: the number of observed missense variants is higher than that which would be expected (Z= -1.01). This variant is not present in ClinVar. There is no case data for this variant. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The variant was reported online in 7 of 132,442 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent (as of October 27, 2016) (minor allele frequency of 0.00002643). Specifically, the variant was observed in 4 of 59,473 individuals of European (Non-Finnish) descent, 3 of 23,344 individuals of African descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

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