ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.1609del (p.Gln537fs) (rs727503129)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150927 SCV000198569 uncertain significance not specified 2013-10-18 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Gln537fs va riant in LDB3 has not been previously reported in any other families with cardio myopathy or in large European American or African American cohorts. This framesh ift variant is predicted to alter the protein?s amino acid sequence beginning at position 537 and lead to a premature termination codon 28 amino acids downstrea m. This alteration is then predicted to lead to a truncated or absent protein (l oss of function). Studies in mice have shown that the spectrum of phenotypes res ulting from homozygous loss of function of LDB3 includes DCM (Zheng 2009; heart specific loss of function) and congenital myopathy (Zhou 2001, complete loss of function). Our laboratory has previously identified one loss of function varian t in an individual with VT and SCA but overall, this type of variant has not yet been reported in individuals with cardio/myopathy. In summary, the predicted im pact to the protein increases the likelihood that this variant is pathogenic but additional studies are required to fully establish its clinical significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000622367 SCV000740592 likely pathogenic not provided 2016-06-19 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769290 SCV000900668 uncertain significance Cardiomyopathy 2017-07-26 criteria provided, single submitter clinical testing
Invitae RCV001245723 SCV001419026 uncertain significance Myofibrillar myopathy, ZASP-related 2020-09-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln537Argfs*28) in the LDB3 gene. It is expected to result in an absent or disrupted protein product. The LDB3 gene has multiple clinically relevant transcripts. The p.Gln537Argfs*28 variant occurs in alternate transcript NM_007078.2, which corresponds to c.*17330del in NM_001080116.1, the primary transcript listed in the Methods. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LDB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 163850). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in LDB3 cause disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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