ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.509G>A (p.Arg170Gln) (rs140904592)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000648835 SCV000894522 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000493885 SCV000582069 uncertain significance not provided 2017-05-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the BAG3 gene. The R170Q variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 4/16,284 (0.02%) alleles from individuals of South Asian ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). This substitution occurs at a position that is only conserved in mammals and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, the R170Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties.
Invitae RCV000648835 SCV000770656 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 170 of the BAG3 protein (p.Arg170Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs140904592, ExAC 0.02%) but has not been reported in the literature in individuals with a BAG3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this intronic variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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