Submissions for variant NM_004281.4(BAG3):c.1035G>C (p.Glu345Asp)

gnomAD frequency: 0.00001  dbSNP: rs1057522401

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000430071	SCV000527539	uncertain significance	not provided	2016-05-06	criteria provided, single submitter	clinical testing	A novel variant of uncertain significance has been identified in the BAG3 gene. The E345D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E345D variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, the E345D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species, and Aspartic acid is tolerated at this position in two mammalian species. Consequently, in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861562	SCV002257689	uncertain significance	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 345 of the BAG3 protein (p.Glu345Asp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BAG3-related conditions. ClinVar contains an entry for this variant (Variation ID: 386029). 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	RCV002393006	SCV002702783	uncertain significance	Cardiovascular phenotype	2025-02-09	criteria provided, single submitter	clinical testing	The p.E345D variant (also known as c.1035G>C), located in coding exon 4 of the BAG3 gene, results from a G to C substitution at nucleotide position 1035. The glutamic acid at codon 345 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.