Submissions for variant NM_004281.4(BAG3):c.652C>T (p.Arg218Trp)

gnomAD frequency: 0.00006  dbSNP: rs397514506

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171829	SCV000054733	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2018-04-05	criteria provided, single submitter	research
Ambry Genetics	RCV000617935	SCV000735735	uncertain significance	Cardiovascular phenotype	2024-12-20	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000648836	SCV000770657	likely benign	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-12-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000648836	SCV002785844	uncertain significance	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-01-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003144117	SCV003829777	uncertain significance	not provided	2023-06-15	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV003144117	SCV005199658	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
GeneDx	RCV003144117	SCV005401205	uncertain significance	not provided	2024-05-15	criteria provided, single submitter	clinical testing	Reported previously in a patient with DCM and in a patient with muscle disease in the published literature (PMID: 23861362, 29382405); Published functional studies suggest a damaging effect by impairing Z-disc assembly and increasing sensitivity to apoptosis (PMID: 21898660); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29382405, 34426522, 32093037, 30615648, 33658040, 21898660, 23861362, 37216087)
OMIM	RCV000032660	SCV000056423	pathogenic	Dilated cardiomyopathy 1HH	2011-12-01	no assertion criteria provided	literature only