ClinVar

Description

The p.R218W variant (also known as c.652C>T), located in coding exon 3 of the BAG3 gene, results from a C to T substitution at nucleotide position 652. The arginine at codon 218 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was reported in a Japanese proband, diagnosed with dilated cardiomyopathy (DCM) at age 73, who also had three affected siblings. This alteration was shown to disrupt Z-disc assembly in cultured cells; however, the physiological relevance of this finding is uncertain (Arimura T et al. Hum. Mutat., 2011 Dec;32:1481-91). This variant was also detected in a individual with skeletal muscle weakness, and in a stillbirth case where it co-occurred with a variant in a different cardiac-related gene (Wu L et al. Can J Neurol Sci. 2018 05;45(3):262-268; Sahlin E et al. PLoS ONE. 2019 Jan;14(1):e0210017). This variant has also been detected in a cohorts not selected for the presence of disease; however, clinical details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Kars ME et al. Proc Natl Acad Sci U S A. 2021 09;118(36)). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.