Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001220639 | SCV001392643 | pathogenic | Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH | 2023-01-14 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Trp36*) in the BAG3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BAG3 are known to be pathogenic (PMID: 21353195, 25008357). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of BAG3-related conditions (PMID: 30442290, 31931689). ClinVar contains an entry for this variant (Variation ID: 949224). |
| Ambry Genetics | RCV003163698 | SCV003864727 | likely pathogenic | Cardiovascular phenotype | 2022-11-14 | criteria provided, single submitter | clinical testing | The p.W36* variant (also known as c.108G>A), located in coding exon 1 of the BAG3 gene, results from a G to A substitution at nucleotide position 108. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. The predicted stop codon occurs in the 5’ end of theBAG3 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This variant has been detected in individuals from dilated cardiomyopathy cohorts; however, details were limited (Domínguez F et al. J Am Coll Cardiol, 2018 11;72:2471-2481; Ramchand J et al. J Am Heart Assoc, 2020 01;9:e013346). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Victorian Clinical Genetics Services, |
RCV004789482 | SCV005400408 | pathogenic | Dilated cardiomyopathy 1HH | 2024-10-09 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with dilated cardiomyopathy, 1HH (DCM; MIM#613881) and myofibrillar myopathy, 6 (MIM#612954). Missense variants with a gain of function effect have been reported in individuals with myopathy, whereas missense variants with a loss of function effect and variants resulting in a premature termination codon, have been reported in individuals with DCM (OMIM, PMID: 30442290). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported in many individuals with dilated cardiomyopathy (DECIPHER, PMID: 30442290). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar, and has been observed in an individual with DCM (PMID: 30442290). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |