ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.690-4678C>T (rs121908334)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036847 SCV000060502 pathogenic Neuromuscular disease 2018-11-21 criteria provided, single submitter clinical testing The p.Ala165Val variant in LDB3 has been reported in at least 6 individuals with myofibrillar myopathy and segregated with disease in 9 affected individuals fro m 1 family (Selcen 2005, Griggs 2007, Fischer 2008, Vincent 2016, LMM data). It has also been identified in 1/113280 of European chromosomes by gnomAD (http://g and reported in ClinVar (Variant ID #4728). An in vitr o function study showed that this variant disrupted Ankrd2 binding (Martinelli 2 014) and a study of mouse myoblasts transfected with the p.Ala165Val mutation sh owed a disrution of Z-disc structure and an accumulation of F-actin (Lin 2014). In summary, this variant meets criteria to be classified as pathogenic for autos omal dominant myofibrillar myopathy. ACMG/AMP criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate.
GeneDx RCV000493600 SCV000582060 pathogenic not provided 2018-03-27 criteria provided, single submitter clinical testing The A165V variant in the LDB3 gene has been previously reported in multiple individuals with myofibrillar myopathy (Selcen et al., 2005; Griggs et al., 2007; Fischer et al., 2008; Vincent et al., 2016). Functional studies demonstrate the A165V variant did not affect the binding between LBD3 and phosphoglucomutase 1 (Arimura et al., 2009). However, Lin et al. demonstrated that the A165V variant results in Z-disc disruption and F-actin accumulation in mouse skeletal muscle, and disruption in the actin cytoskeleton in muscle cells (Lin et al., 2014). The A165V 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). This substitution occurs at a position that is conserved across species. However, the A165V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, the presence of A165V is consistent with the diagnosis of myofibrillar myopathy in this individual.
Athena Diagnostics Inc RCV000493600 SCV000613999 pathogenic not provided 2014-12-09 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769278 SCV000900654 uncertain significance Cardiomyopathy 2017-07-04 criteria provided, single submitter clinical testing
Invitae RCV000004993 SCV000965091 pathogenic Myofibrillar myopathy, ZASP-related 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 165 of the LDB3 protein (p.Ala165Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs121908334, ExAC 0.001%). This variant has been observed in several individuals affected with myofibrillar myopathy (PMID: 15668942, 25208129). ClinVar contains an entry for this variant (Variation ID: 4728). This variant has been reported to affect LDB3 protein function (PMID: 24668811, 24647531). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000493600 SCV001247303 pathogenic not provided 2020-09-01 criteria provided, single submitter clinical testing
OMIM RCV000004993 SCV000025169 pathogenic Myofibrillar myopathy, ZASP-related 2005-02-01 no assertion criteria provided literature only
Wellcome Centre for Mitochondrial Research,Newcastle University RCV000239669 SCV000298022 pathogenic Myofibrillar myopathy 2016-08-16 no assertion criteria provided clinical testing

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