Submissions for variant NM_004281.4(BAG3):c.1088A>C (p.Glu363Ala)

dbSNP: rs1345725468

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV001507781	SCV001713544	uncertain significance	not provided	2019-11-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001882547	SCV002204047	uncertain significance	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 363 of the BAG3 protein (p.Glu363Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 1163045). 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	RCV002424949	SCV002727885	uncertain significance	Cardiovascular phenotype	2024-07-14	criteria provided, single submitter	clinical testing	The p.E363A variant (also known as c.1088A>C), located in coding exon 4 of the BAG3 gene, results from an A to C substitution at nucleotide position 1088. The glutamic acid at codon 363 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323892	SCV004028878	uncertain significance	not specified	2023-07-03	criteria provided, single submitter	clinical testing	Variant summary: BAG3 c.1088A>C (p.Glu363Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1088A>C in individuals affected with Myofibrillar Myopathy, BAG3-Related and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.