ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.1166G>A (p.Ser389Asn) (rs140251789)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183313 SCV000235741 uncertain significance not provided 2017-01-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the BAG3 gene. The S389N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the Exome Aggregation Consortium (ExAC) data set. However, the S389N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species and where asparagine is the wild type in multiple species. Finally, in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV000809761 SCV000949935 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 389 of the BAG3 protein (p.Ser389Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs140251789, ExAC 0.07%). This variant has not been reported in the literature in individuals with BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 201677). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The asparagine 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.

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