ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.743A>G (p.His248Arg) (rs369947845)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183325 SCV000235756 uncertain significance not provided 2016-10-20 criteria provided, single submitter clinical testing The H248R variant has been reported previously in an individual with an enlarged heart and myocardial hypertrophy, who also harbored a variant in the TTN gene; however, parental testing was not completed and functional characterization of the BAG3 variant was not performed (Hellenthal et al., 2016). The H248R 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 H248R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Histidine are tolerated across species. 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 a pathogenic variant or a rare benign variant.
Invitae RCV000648842 SCV000770663 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 248 of the BAG3 protein (p.His248Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs369947845, ExAC 0.02%). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (HCM) (PMID: 28750076). However, in that individual, a pathogenic allele was also identified in MYBPC3 which suggests that this c.743A>G variant in BAG3 was not the primary cause of disease. In addition, this variant also has been reported in a case of sudden unexplained death, in which cardiac autopsy was performed (PMID: 29016939). ClinVar contains an entry for this variant (Variation ID: 201687). 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.

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