ClinVar Miner

Submissions for variant NM_004281.4(BAG3):c.367C>T (p.Arg123Ter) (rs387906875)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211711 SCV000061554 likely pathogenic Primary dilated cardiomyopathy 2017-01-27 criteria provided, single submitter clinical testing The p.Arg123X variant in BAG3 has been identified in 4 adults with DCM and segre gated with disease in 5 affected relatives (Norton 2011, LMM data). This variant has also been identified in 2/66492 European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs387906875). This no nsense variant leads to a premature termination codon at position 123, which is predicted to lead to a truncated or absent protein. Loss of function variants in BAG3 are strongly associated with DCM. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg123X variant is likely pathogenic.
Ambry Genetics RCV000247382 SCV000318449 pathogenic Cardiovascular phenotype 2019-01-21 criteria provided, single submitter clinical testing The p.R123* pathogenic mutation (also known as c.367C>T), located in coding exon 2 of the BAG3 gene, results from a C to T substitution at nucleotide position 367. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been reported in individuals with dilated cardiomyopathy (DCM) (Norton N et al. Am J Hum Genet. 2011;88(3):273-82; Janin A et al. Clin. Genet., 2017. Dec;92(6):616-23). Loss of function alterations have been reported in numerous cases of familial DCM, including many families with strong segregation with disease (Norton N et al. Am J Hum Genet. 2011;88(3):273-82; Villard E et al. Eur Heart J. 2011;32(9):1065-76; Chami N et al. Can J Cardiol. 2014;30(12):1655-61; Feldman AM et al. J Cell Physiol. 2014;229(11):1697-702; Franaszczyk M et al. J Transl Med. 2014;12:192; van Spaendonck-Zwarts KY et al. Eur Heart J. 2014;35(32):2165-73). In addition, in Norton et al 2011, BAG3 knockdown in a zebrafish model showed heart failure with decreased fractional shortening and pericardial effusion. 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.
GeneDx RCV000254992 SCV000322083 pathogenic not provided 2021-06-21 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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; Reported in ClinVar (ClinVar Variant ID# 30397; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28724793, 25008357, 21459883, 24623017, 24558114, 25525159, 25728519, 28436997, 25448463, 27391596, 31983221, 31514951, 32859500, 27535533, 21353195)
Invitae RCV000627789 SCV000550842 pathogenic Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2020-03-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 123 (p.Arg123*) of 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 particular variant has been reported in the literature in a family affected with dilated cardiomyopathy (PMID: 21353195). ClinVar contains an entry for this variant (Variation ID: 30397). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000627789 SCV000893146 pathogenic Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000023350 SCV000044641 pathogenic Dilated cardiomyopathy 1HH 2011-03-11 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000254992 SCV000924755 likely pathogenic not provided 2018-01-29 no assertion criteria provided provider interpretation
Genomics England Pilot Project,Genomics England RCV000023350 SCV001760248 likely pathogenic Dilated cardiomyopathy 1HH no assertion criteria provided clinical testing

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