ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.230C>T (p.Pro77Leu) (rs141355480)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000150175 SCV000612482 benign not specified 2017-02-24 criteria provided, single submitter clinical testing
GeneDx RCV000150175 SCV000517070 likely benign not specified 2015-07-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000472056 SCV000550829 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 77 of the BAG3 protein (p.Pro77Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs141355480, 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. However, it was reported in an individual affected with progressive multifocal leukoencephalopathy, a pathology for which no association with BAG3 has been suggested elsewhere (PMID: 27042682). ClinVar contains an entry for this variant (Variation ID: 162774). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150175 SCV000197085 likely benign not specified 2014-06-05 criteria provided, single submitter clinical testing Pro77Leu in exon 2 of BAG3: This variant is not expected to have clinical signif icance due to a lack of conservation across species, including mammals. Of note, >45 mammals and other species have a leucine (Leu) at this position despite hig h nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has also been identi fied in 5/8600 European American chromosomes by the NHLBI Exome Sequencing Proje ct (http://evs.gs.washington.edu/EVS/; dbSNP rs141355480).

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