ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.690-4733G>A (rs121908333)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255980 SCV000322056 pathogenic not provided 2017-01-10 criteria provided, single submitter clinical testing The A147T pathogenic variant in the LDB3 gene has been reported in multiple individuals with myofibrillar myopathy, at least 3 of whom had cardiac involvement (Selcen et al., 2005). In addition, Lin et al. (2014) performed function studies that demonstrated the A147T variant disrupts the actin cytoskeleton in mouse muscle cells. A147T results in a non-conservative amino acid substitution at a position that is conserved across species. Furthermore, the A147T pathogenic variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, A147T in the LDB3 gene is interpreted as a pathogenic variant.
Invitae RCV000004992 SCV000545674 pathogenic Myofibrillar myopathy, ZASP-related 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 147 of the LDB3 protein (p.Ala147Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (rs121908333, ExAC no frequency). This variant has been reported in many unrelated individuals affected with myofibrillar myopathy (PMID: 15668942, 23263837). ClinVar contains an entry for this variant (Variation ID: 4727). Experimental studies have shown that this missense change disrupts actin stress fibers in transfected mouse muscle cells (PMID: 24668811). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770149 SCV000901575 uncertain significance Cardiomyopathy 2017-07-27 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255980 SCV001247302 pathogenic not provided 2019-01-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000255980 SCV001476528 pathogenic not provided 2019-09-10 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Conflicting predictions of the effect on the protein. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Segregation with disease in affected individuals from a single family.
OMIM RCV000004992 SCV000025168 pathogenic Myofibrillar myopathy, ZASP-related 2005-02-01 no assertion criteria provided literature only

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