ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.1823C>T (p.Pro608Leu) (rs145983824)

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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 RCV000038742 SCV000062420 uncertain significance not specified 2014-02-17 criteria provided, single submitter clinical testing The Pro608Leu variant in LDB3 has now been identified by our laboratory in 1 Cau casian adult with LVNC and biventricular enlargement, who also carried a likely pathogenic variant in another gene, and 1 Black adult with DCM (LMM unpublished data; including this individual). In addition, this variant has also been identi fied in 1/8600 European American chromosomes and in 2/4406 African American chro mosomes by the NHLBI Exome Sequencing Project ( ; dbSNP rs145983824). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may imp act the protein, though this information is not predictive enough to determine p athogenicity. Additional information is needed to fully assess the clinical sign ificance of the Pro608Leu variant.
GeneDx RCV000767179 SCV000536381 uncertain significance not provided 2018-05-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LDB3 gene. The P608L variant has not been published as pathogenic or been reported as benign to our knowledge. This 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; Exome Aggregation Consortium). The P608L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with LDB3-related disorders (Stenson et al., 2014).
Invitae RCV000558390 SCV000638690 uncertain significance Myofibrillar myopathy, ZASP-related 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 608 of the LDB3 protein (p.Pro608Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. The LDB3 gene has multiple clinically relevant isoforms. The p.Pro608Leu variant occurs in alternate transcript NM_007078.2, which corresponds to position c.*18736C>T, in NM_001080116.1, the primary transcript listed in the Methods. This variant is present in population databases (rs145983824, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 17097056). This variant is also known as p.Pro615Leu in the literature. ClinVar contains an entry for this variant (Variation ID: 45533). 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. 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.
OMIM RCV000170304 SCV000222652 pathogenic Familial hypertrophic cardiomyopathy 24 2006-12-29 no assertion criteria provided literature only

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