Submissions for variant NM_004281.4(BAG3):c.827G>A (p.Arg276Gln)

gnomAD frequency: 0.00007  dbSNP: rs372970842

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690953	SCV000818684	uncertain significance	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 276 of the BAG3 protein (p.Arg276Gln). This variant is present in population databases (rs372970842, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. 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: 570152). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BAG3 protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193221	SCV001361935	likely benign	not specified	2023-07-05	criteria provided, single submitter	clinical testing	Variant summary: BAG3 c.827G>A (p.Arg276Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 250258 control chromosomes (gnomAD). The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in BAG3 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. c.827G>A has been reported in the literature in the homozygous state in an individual affected with an autosomal recessive inherited retinal disease without strong evidence for causality and with no reported cardiac phenotype (Van de Sompele_2019). Thus, this report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002406556	SCV002675733	uncertain significance	Cardiovascular phenotype	2024-01-18	criteria provided, single submitter	clinical testing	The p.R276Q variant (also known as c.827G>A), located in coding exon 3 of the BAG3 gene, results from a G to A substitution at nucleotide position 827. The arginine at codon 276 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is 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 alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV004597858	SCV005093100	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BAG3: BP4