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

gnomAD frequency: 0.00082  dbSNP: rs200596619

Total submissions: 12

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530438	SCV000638668	benign	Myofibrillar myopathy 4	2024-01-22	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
Ambry Genetics	RCV002336344	SCV002638126	likely benign	Cardiovascular phenotype	2018-04-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV001530010	SCV004127001	benign	not provided	2022-04-01	criteria provided, single submitter	clinical testing	LDB3: BP4, BS1, BS2
Blueprint Genetics	RCV000157287	SCV000207018	likely benign	Left ventricular noncompaction cardiomyopathy	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530010	SCV001744491	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000183527	SCV001921269	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001530010	SCV001932566	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001530010	SCV001953970	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001530010	SCV001976021	likely benign	not provided		no assertion criteria provided	clinical testing