Submissions for variant NM_004281.4(BAG3):c.699C>A (p.Tyr233Ter)

dbSNP: rs876661342

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463650	SCV000550825	pathogenic	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-08-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr233*) in the BAG3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BAG3 are known to be pathogenic (PMID: 21353195, 25008357). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 31514951). ClinVar contains an entry for this variant (Variation ID: 234982). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000223884	SCV000564689	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar (ClinVar Variant ID# 234982; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31514951)
Ambry Genetics	RCV002372238	SCV002668046	pathogenic	Cardiovascular phenotype	2023-03-13	criteria provided, single submitter	clinical testing	The p.Y233* pathogenic mutation (also known as c.699C>A), located in coding exon 3 of the BAG3 gene, results from a C to A substitution at nucleotide position 699. This changes the amino acid from a tyrosine to a stop codon within coding exon 3. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000463650	SCV005660257	pathogenic	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-02-28	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223884	SCV000280054	likely pathogenic	not provided	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 the data supporting pathogenicity of nonsense BAG3 variants, the case data, and the absence in patients unselected for cardiomyopathy, we consider this variant likely disease causing. This specific variant (p.Tyr233Ter) is novel. However, it has been seen in one of the families reported in an initial publication on BAG3 (Norton et al 2011). That family had two brothers with DCM and both had this variant and p.Ala262Thr in BAG3. No phase data is available. The variant is not listed 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).