ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.653G>A (p.Arg218Gln) (rs201638005)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000243434 SCV000319682 uncertain significance Cardiovascular phenotype 2018-03-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172520 SCV000050892 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000155787 SCV000329097 uncertain significance not specified 2015-08-05 criteria provided, single submitter clinical testing The R218Q variant of unknown significance has been reported in one individual with DCM but was also present in 1/355 controls (Norton et al., 2011). Nevertheless, the R218Q variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R218Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. Additionally, a missense variant in this same residue (R218W) has been reported in a single case of a Japanese individual with familial DCM and was absent from 400 controls (Arimura et al., 2011), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant.
Invitae RCV000472504 SCV000550832 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-06-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 218 of the BAG3 protein (p.Arg218Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs201638005, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 179009). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155787 SCV000205498 likely benign not specified 2018-09-05 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000623668 SCV000740459 uncertain significance Left ventricular noncompaction 2017-05-23 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000172520 SCV000924757 uncertain significance not provided 2016-05-27 no assertion criteria provided provider interpretation - p.Arg218Gln in the BAG3 gene Given the lack of case data and relatively high frequency in control populations, we consider this variant to be of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen the variant in one individual with LVNC. Testing was done by Invitae. The variant has not been reported in the literature. Per the Invitae report, "This sequence change replaces arginine with glutamine at codon 218 of the BAG3 protein (p.Arg218Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0")." The Arg218Gln variant was reported online in 24 of 60,314 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 5/27/16). Specifically, the variant was observed in 12 of 8,247 South Asian people, 4 of 5,774 Latino people, 1 of 8616 East Asian people, and 7 of 33,081 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. This is a relatively high carrier frequency that spans several ancestries, decreasing the level of suspicion for pathogenicity. In addition, another variant affecting the same codon, Arg218Trp, is present in 8 of 60,301 individuals, specifically 5 of 4312 East Asian people, 1 of 3306 Finnish people, and 2 of 33,089 non-Finnish European people. This suggests that this codon is toleratant of variation.

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