ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.784G>A (p.Ala262Thr) (rs876661343)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766537 SCV000329098 uncertain significance not provided 2018-02-21 criteria provided, single submitter clinical testing The A262T variant of uncertain significance in the BAG3 gene has been reported previously in association with DCM (Norton et al., 2011). A262T was reported in two brothers with DCM, who each underwent a heart transplantation, and had a family history significant for DCM in their father; however, the father was unavailable for testing (Norton et al., 2011).The A262T variant is not observed in large population cohorts (Lek et al., 2016). The A262T variant 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000464394 SCV000550831 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-08-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 262 of the BAG3 protein (p.Ala262Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in two siblings with dilated cardiomyopathy (DCM) (PMID: 21353195). Currently there is no evidence whether this variant segregates with disease or not. ClinVar contains an entry for this variant (Variation ID: 234983). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The threonine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223716 SCV000280055 uncertain significance not specified 2015-07-22 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given there is only minimal case data and the variant has been repeatedly seen with a nonsense variant, we consider this variant a variant of uncertain significance. The variant has been seen in at least one unrelated cases of DCM. There is weak segregation data. It has been observed in two brothers with dilated cardiomyopathy, AV block, Q waves (Norton et al 2011). They were both severely affected and underwent heart transplant in their 40s. These brothers also have a BAG3 p.Tyr233Ter variant, though this was not reported in Norton et al (2011). In silico analysis predicts the variant doesn't negatively affect the protein. The alanine at codon 262 is not conserved across species. Other variants have been reported in association with disease at nearby codons (p.Arg258Trp, HGMD). The variant was reported online in 9 of 60384 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 July 14th, 2015). Specifically, the variant was observed in 8 of 33,160 Europeans (MAF 0.0001206). 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

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