ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.1634C>G (p.Pro545Arg) (rs759348679)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000275438 SCV000360609 uncertain significance Myofibrillar Myopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000332813 SCV000360610 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000423745 SCV000531829 uncertain significance not provided 2018-01-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the BAG3 gene. The P545R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P545R variant is observed in 5/25786 (0.02%) alleles from individuals of Finnish background in large population cohorts (Lek et al., 2016). The P545R 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000461611 SCV000550848 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 545 of the BAG3 protein (p.Pro545Arg). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs759348679, ExAC 0.02%), 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 BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 298963). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Klaassen Lab,Charite University Medicine Berlin RCV000853141 SCV000995854 uncertain significance Primary dilated cardiomyopathy 2019-07-03 criteria provided, single submitter research

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