ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.67C>T (p.Pro23Ser) (rs747846089)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000319672 SCV000329096 uncertain significance not provided 2018-09-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the BAG3 gene. The P23S variant has previously been published in an individual with hereditary sensory neuropathy (Antonidadi et al., 2015); it has not been reported in associated with cardiac disease to our knowledge. P23S has been identified in other unrelated individuals referred for cardiomyopathy or arrhythmia genetic testing at GeneDx; however, one individual also harbored a pathogenic variant in another gene that segregated with disease in an affected relative. This variant is observed in 7/120,896 (0.006%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The P23S 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. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000524859 SCV000650670 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 23 of the BAG3 protein (p.Pro23Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs747846089, ExAC 0.01%). This variant has been reported in an individual affected with hereditary sensory neuropathy (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 279697). 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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