ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.418G>A (p.Gly140Ser) (rs780169403)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658579 SCV000780356 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
GeneDx RCV000658579 SCV000620488 uncertain significance not provided 2017-08-30 criteria provided, single submitter clinical testing The G140S variant has not been published as pathogenic or been reported as benign to our knowledge. The G140S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G140S 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. Nevertheless, this substitution occurs at a position that is not conserved across species, where S140 is wild-type for multiple other species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000648846 SCV000770667 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2017-10-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 140 of the BAG3 protein (p.Gly140Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs780169403, ExAC 0.002%). This variant has not been reported in the literature in individuals with BAG3-related disease. 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 serine 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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