ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.466G>A (p.Ala156Thr) (rs200596619)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183527 SCV000235990 likely benign not specified 2017-04-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000530438 SCV000638668 benign Myofibrillar myopathy, ZASP-related 2020-03-23 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000183527 SCV001433252 likely benign not specified 2020-01-03 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157287 SCV000207018 likely benign Cardiomyopathy, left ventricular noncompaction 2014-02-24 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183527 SCV000280177 uncertain significance not specified no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LDB3 p.Ala156Thr Based on the data reviewed below we consider this variant a variant of uncertain significance. LIM domain binding 3, also known as LDB3 or ZASP, is a protein which in humans is encoded by the LDB3 gene. Mutations in the LDB3 gene have been reported in patients with autosomal dominant familial dilated cardiomyopathy, however it is currently not known what percentage of individuals with familial DCM have a mutation in the LDB3 gene (Hershberger R et al., 2009). Variants in LDB3 have also been associated with Myofibrillar myopathy (MFM), a morphologically distinct disorder in which disintegration of the Z-disk and then of the myofibrils is followed by abnormal accumulation of multiple proteins. Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles. Matteo and colleagues studied 100 probands, 15 with identified LVNC. Creatinine kinase levels were normal in all the probands and there was no clinical evidence of a skeletal myopathy. Mutations in ZASP (LDB3) were identified in 6 of the 100 probands, four of whom with identified LVNC and two with DCM (Vatta, M et al., 2003) They did not test other genes associated with DCM and LVNC. No mutations were identified in 200 ethnically matched control individuals (400 chromosomes). Arimurat and colleagues studied ZASP/Cypher gene in 96 unrelated Japanese patients with dilated cardiomyopathy. Five variations were identified in codons -5, 55, 588, 626, 644. They determined V55I and V588I to be polymorphisms because they were also found in unrelated healthy controls. The D626N variation identified in a proband patient of familial DCM was not found in 400 unrelated healthy controls. This variant was shown to alter the function of the LIM domain. They described the phenotype of the family with this variant as having "late onset DCM"; after age 50. No clinical features of LVNC were indicated. Selcen and Engel, 2005 studied ZASP sequence variants in 54 patients with myofibrillar myopathy (MFM) and detected 3 heterozygous missense mutations in 11 patients. Most patients had proximal and distal weakness. Ten carried either of two mutations in exon 6 (A147T and A165V) at or within a motif important in linking ZASP to the Z-disk and one carried a missense mutation in exon 9 (R268C). The A147T variant segregated with disease in 3 additional affected family members. The A165V variant is within, and the A147T mutation is immediately before the ZM motif needed for interaction with actinin. The variants were not present in 220 alleles from control subjects. This variant Ala156Thr is novel and has not been reported as a disease-causing or as a benign polymorphism. The variant p.Ala156Thr is in exon 4 of the LDB3 gene (NM_007078.2) and is within the ZM motif needed for interaction with actinin. This is a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Threonine residue. In silico analysis with PolyPhen-2 predicts the variant to be benign. Mutation Taster predicts this variant to be a polymorphism. The alanine at codon 156 is NOT conserved across species. Other variants have been reported in association with disease at nearby codons (Ala147Thr; Ala165Val). In total the variant has not been 710 published controls. Ala156Thr is seen in 4 of 8588 European alleles and 0 of 4400 African American alleles in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6,500 Caucasian and African American individuals (as of 7/7/13). This variant is listed in dbSNP (rs200596619). The variant was not observed in the following published control samples: Matteo et al did not report this variant in 200 control individuals, Selcen and Engel did not report this variant in 110 control subjects, Amriuat et al. did not report this variant in 400 controls.

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