Submissions for variant NM_004281.4(BAG3):c.826C>T (p.Arg276Trp)

gnomAD frequency: 0.00001  dbSNP: rs759573189

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223628	SCV000271523	uncertain significance	not specified	2015-06-25	criteria provided, single submitter	clinical testing	The p.Arg276Trp variant in BAG3 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/16486 South Asian chromosomes in one homozygous individual by the Exome Aggregation Consortium (http://exac.br oadinstitute.org). Computational prediction tools and conservation analyses do n ot provide strong support for or against an impact to the protein. In summary, a dditional information is needed to fully assess the clinical significance of thi s variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001297096	SCV001486081	uncertain significance	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 276 of the BAG3 protein (p.Arg276Trp). This variant is present in population databases (rs759573189, gnomAD 0.01%). 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: 228459). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Revvity Omics, Revvity	RCV001580096	SCV003829771	uncertain significance	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004020608	SCV005021899	uncertain significance	Cardiovascular phenotype	2023-10-02	criteria provided, single submitter	clinical testing	The p.R276W variant (also known as c.826C>T), located in coding exon 3 of the BAG3 gene, results from a C to T substitution at nucleotide position 826. The arginine at codon 276 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. 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.
GeneDx	RCV001580096	SCV005372745	uncertain significance	not provided	2023-07-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001580096	SCV001809659	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001580096	SCV001924941	uncertain significance	not provided		no assertion criteria provided	clinical testing