ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.655C>T (p.Arg219Ter) (rs727503123)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150918 SCV000198544 uncertain significance not specified 2014-04-16 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg219X var iant in LDB3 has not been reported in individuals with cardiomyopathy or in larg e population studies. This nonsense variant leads to a premature termination cod on at position 219, which is predicted to lead to a truncated or absent protein (loss-of-function). Studies of mouse models support that absence of LDB3 in the heart leads to DCM (Zheng 2009); however, this has not been well studied in huma ns. Our laboratory has detected homozygous/compound heterozygous loss-of-functio n variants in LDB3 in 2 neonates with DCM +/- LVNC and 1 individual with VT and SCA carried heterozygous loss of function variant. These data suggest that loss- of-function variants in LDB3 are pathogenic in the homozygous/compound heterozyg ous state but additional studies are needed to fully establish their clinical si gnificance.
GeneDx RCV000766441 SCV000680933 uncertain significance not provided 2017-03-06 criteria provided, single submitter clinical testing The R219X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R219X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R219X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, loss-of-function variants in the LDB3 gene have not been reported in the Human Gene Mutation Database in association with LDB3-related disorders (Stenson et al., 2014).

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