ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.191C>T (p.Ser64Phe) (rs780615753)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000492825 SCV000583325 uncertain significance not provided 2017-05-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the BAG3 gene. The S64F variant has not been published as pathogenic or been reported as benign to our knowledge. This 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 S64F 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. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000529996 SCV000650662 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2017-07-10 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 64 of the BAG3 protein (p.Ser64Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs780615753, ExAC 0.004%). This variant has not been reported in the literature in individuals with BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 430505). 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: "Probably 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.

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