ClinVar Miner

Submissions for variant NM_004281.4(BAG3):c.821C>T (p.Ser274Leu) (rs143919208)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172521 SCV000051366 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037900 SCV000061562 uncertain significance not specified 2015-10-28 criteria provided, single submitter clinical testing The p.Ser274Leu variant in BAG3 has been identified by our laboratory in 1 Cauca sian infant with HCM and clinical features of Noonan syndrome and in 1 individua l with HCM. This variant has been identified in 0.1% (13/10264) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs143919208). Computational prediction tools and conservation analysis suggest that the p.Ser274Leu variant may not impact the protein, though this inf ormation is not predictive enough to rule out pathogenicity. In summary, the cli nical significance of the p.Ser274Leu variant is uncertain.
GeneDx RCV000172521 SCV000520173 uncertain significance not provided 2016-12-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the BAG3 gene. The S274L variant has been previously reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia or family history of sudden cardiac death who underwent exome sequencing (Ng et al, 2013); however, no follow-up cardiac evaluation was reported. The S274L variant is also reported as a variant of uncertain significance in ClinVar by a different clinical laboratory who observed this variant in one individual with HCM and one infant with HCM and features of Noonan syndrome (ClinVar SCV000061562.4; Landrum et al., 2016), although no segregation data was available. Additionally, S274L has been observed in two other individuals referred for cardiomyopathy genetic testing at GeneDx who both harbored additional cardiogenetic variants. In one family, this variant segregated independently with DCM in one affected relative, however, no additional segregation data is available for either case observed at GeneDx. The S274L variant was observed in individuals of African ancestry at a frequency of approximately 0.08% (1/1322) of alleles in the 1000 Genomes project, 0.14% (6/4406) of alleles in the NHLBI Exome Sequencing Project, and 0.13% (13/10264) of alleles in the Exome Aggregation Consortium, indicating it may be a rare benign variant in this population. Furthermore, this substitution occurs at a position that is not conserved across species. Nevertheless, S274L is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV001088222 SCV000561206 likely benign Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2019-12-31 criteria provided, single submitter clinical testing

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