ClinVar Miner

Submissions for variant NM_004281.4(BAG3):c.841G>A (p.Ala281Thr)

gnomAD frequency: 0.00001  dbSNP: rs1248777510
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001928327 SCV002181280 uncertain significance Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH 2025-01-28 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 281 of the BAG3 protein (p.Ala281Thr). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 28416588). ClinVar contains an entry for this variant (Variation ID: 1413809). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BAG3 protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV004996103 SCV005540438 uncertain significance Cardiovascular phenotype 2024-07-22 criteria provided, single submitter clinical testing The p.A281T variant (also known as c.841G>A), located in coding exon 3 of the BAG3 gene, results from a G to A substitution at nucleotide position 841. The alanine at codon 281 is replaced by threonine, an amino acid with similar properties. This variant has been detected in dilated cardiomyopathy cohorts; however, details were limited (Dal Ferro M et al. Heart, 2017 Nov;103:1704-1710; Perret C et al. Clin Genet, 2024 Feb;105:185-189). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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