ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.690-4826G>A (rs200458194)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171990 SCV000050971 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171990 SCV000235993 uncertain significance not provided 2014-07-30 criteria provided, single submitter clinical testing p.Ala231Thr (GCC>ACC): c.691 G>A in exon 6 of the LDB3 gene (NM_001171610.1). To our knowledge the A231T variant has not been published as a mutation or as a benign polymorphism. The A231T variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the A231T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, this variant is located in an alternate transcript of the LDB3 gene where no mutations have been reported. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV001324560 SCV001515517 uncertain significance Myofibrillar myopathy, ZASP-related 2020-07-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 116 of the LDB3 protein (p.Ala116Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs200458194, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 191696). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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