ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.961C>T (p.Pro321Ser) (rs376832654)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183320 SCV000235750 uncertain significance not provided 2014-08-22 criteria provided, single submitter clinical testing p.Pro321Ser (CCA>TCA): c.961 C>T in exon 4 of the BAG3 gene (NM_004281.3). A variant of unknown significance has been identified in the BAG3 gene. The P321S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. P321S was not observed with any significant frequency in 6503 individuals of European and African American descent in the NHLBI Exome Sequencing Project. Missense mutations in nearby residues have not been reported indicating this region of the protein may tolerate change. However, the P321S 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Mutations in BAG3 account for approximately 2.5% of familial DCM cases (Hershberger RE and Morales A, 2013). Mutations in BAG3 may also cause myofibrillar myopathy type 6, which is characterized by early-onset, severe, progressive, diffuse muscle weakness associated with cardiomyopathy, severe respiratory insufficiency and spine rigidity (Hershberger RE and Morales A, 2013). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000459569 SCV000550856 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 321 of the BAG3 protein (p.Pro321Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs376832654, ExAC <0.01%) but has not been reported in the literature in individuals with a BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 201683). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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