ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.626C>T (p.Pro209Leu) (rs121918312)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183317 SCV000235747 pathogenic not provided 2016-05-25 criteria provided, single submitter clinical testing The P209L mutation in the BAG3 gene has been reported previously in patients with myofibrillar myopathy (Selcen et al., 2010) as well as in patients initially presenting with axonal neuropathy with giant axons (Jaffer et al., 2012). Selcen et al. conducted further studies of the P209L mutation in COS cells and showed that the mutation caused abnormal aggregation of the resultant protein (Selcen et al., 2010). This mutation is a non-conservative amino acid substitution as a Proline residue with a unique ring shape is replaced with a Leucine residue at a position that is highly conserved across species. In silico analysis predicts this mutation is probably damaging to the protein structure/function. Additionally the P209L mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret P209L as a disease-causing mutation.
Invitae RCV000648847 SCV000770668 pathogenic Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2019-06-24 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 209 of the BAG3 protein (p.Pro209Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been reported in the literature in numerous individuals affected with myofibrillar myopathy. In the majority of these cases, this variant has been reported to arise de novo in individuals affected with disease (PMID: 19085932, 20605452, 21361913, 22734908, 25208129, 25728519, 26545904, 27443559). ClinVar contains an entry for this variant (Variation ID: 5981). Experimental studies in vitro have shown that this missense change disrupts BAG3 protein function, and results in the formation of protein aggregates. This variant has also been studied in animal models where over-expression of the p.Pro209Leu protein leads to myofibrillar disintegration and a recapitulation of the human myofibrillar myopathy phenotype (PMID: 19085932, 25273835, 27321750, 27443559, 21898660). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000006347 SCV000807268 pathogenic Myofibrillar myopathy, BAG3-related 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory as a de novo change in a 4-year-old male with muscular weakness, tight heel cords, restrictive cardiomyopathy.
Broad Institute Rare Disease Group,Broad Institute RCV000006347 SCV000924465 pathogenic Myofibrillar myopathy, BAG3-related 2018-06-15 criteria provided, single submitter research The heterozygous p.Pro209Leu variant was identified by our study in one individual with myofibrillar myopathy. Trio exome analysis showed this variant to be de novo. The p.Pro209Leu variant is pathogenic based off of our findings, multiple de novo reports in ClinVar, and the literature.
Kariminejad - Najmabadi Pathology & Genetics Center RCV000788083 SCV000927081 likely pathogenic Charcot-Marie-Tooth disease 2018-12-06 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000183317 SCV001246714 pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing
OMIM RCV000006347 SCV000026529 pathogenic Myofibrillar myopathy, BAG3-related 2012-06-01 no assertion criteria provided literature only
GeneReviews RCV000006347 SCV000055844 pathologic Myofibrillar myopathy, BAG3-related 2012-10-29 no assertion criteria provided curation Converted during submission to Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.