ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.415C>T (p.Arg139Trp) (rs556465096)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000399357 SCV000360560 likely benign Myofibrillar Myopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000312020 SCV000360561 likely benign Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000426283 SCV000528907 uncertain significance not specified 2016-06-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the BAG3 gene. The R139W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R139W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or with any significant frequency in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. The R139W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000465666 SCV000550834 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-05-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 139 of the BAG3 protein (p.Arg139Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs556465096, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with a BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 298956). 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 has uncertain impact on BAG3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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