ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.1588G>A (p.Val530Met) (rs144678100)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618030 SCV000736608 uncertain significance Cardiovascular phenotype 2016-06-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Illumina Clinical Services Laboratory,Illumina RCV000329418 SCV000360607 uncertain significance Myofibrillar Myopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000367822 SCV000360608 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000469156 SCV000550840 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2016-10-12 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 530 of the BAG3 protein (p.Val530Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs144678100, ExAC 0.02%) but has not been reported in the literature in individuals with a BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 162787). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The methionine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150187 SCV000197108 likely benign not specified 2013-04-03 criteria provided, single submitter clinical testing Val530Met in exon 4 of BAG3: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , multiple mammals, including primates, carry a methionine (Met) at this positio n despite high nearby amino acid conservation. In addition, computational analys es (AlignGVGD, PolyPhen2, SIFT) do not suggest a high likelihood of impact to th e protein. The Val530Met variant has also been identified in 4/8600 European Ame rican chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washingto n.edu/EVS/; dbSNP rs144678100).

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