Submissions for variant NM_004281.3(BAG3):c.679C>G (p.Gln227Glu) (rs149517238)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000244314	SCV000320475	uncertain significance	Cardiovascular phenotype	2015-11-20	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (benign)
GeneDx	RCV000426389	SCV000529860	uncertain significance	not provided	2018-07-17	criteria provided, single submitter	clinical testing	The Q227E variant in the BAG3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Q227E variant is observed in 9/126578 (0.007%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016). The Q227E variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret Q227E as a variant of uncertain significance.
Invitae	RCV000685071	SCV000812543	uncertain significance	Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH	2018-05-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with glutamic acid at codon 227 of the BAG3 protein (p.Gln227Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs149517238, ExAC 0.005%). This variant has not been reported in the literature in individuals with BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 264497). 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: "Possibly 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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