Submissions for variant NM_004281.3(BAG3):c.460G>A (p.Val154Met) (rs376198104)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000418380	SCV000531966	likely benign	not specified	2016-10-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000477421	SCV000550841	uncertain significance	Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH	2016-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces valine with methionine at codon 154 of the BAG3 protein (p.Val154Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs376198104, ExAC 0.05%) but has not been reported in the literature in individuals with a BAG3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.