ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.1225C>A (p.Gln409Lys) (rs139104492)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000344660 SCV000329396 uncertain significance not provided 2017-04-14 criteria provided, single submitter clinical testing The Q409K variant in the LDB3 gene has been reported previously (as Q414K due to alternative nomenclature) in an individual who underwent genetic testing for sporadic inclusion body myositis; however, segregation information, in vitro functional studies, and additional clinical information were not included (Weihl et al., 2015). The Q409K variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q409K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret Q409K as a variant of uncertain significance.
Invitae RCV000539708 SCV000638683 uncertain significance Myofibrillar myopathy, ZASP-related 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 409 of the LDB3 protein (p.Gln409Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. The LDB3 gene has multiple clinically relevant isoforms. The p.Gln409Lys variant occurs in alternate transcript NM_007078.2, which corresponds to position c.*10670C>A in NM_001080116.1, the primary transcript listed in the Methods. This variant is present in population databases (rs139104492, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with inclusion body myositis (PMID: 25617006). This variant is also known as c.1240C>A (p.Q414K) in the literature. Clinvar contains an entry for this variant (Variation ID: 279835). 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 disruptive, 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256802 SCV001433255 uncertain significance Dilated cardiomyopathy 1A 2020-03-27 criteria provided, single submitter clinical testing

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