ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.2092G>A (p.Ala698Thr) (rs45577134)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038750 SCV000062428 uncertain significance not specified 2014-08-01 criteria provided, single submitter clinical testing The Ala698Thr variant in LDB3 has been reported in 2 individuals with DCM, both of whom also carry an additional variant in another cardiomyopathy-associated ge ne (Hershberger 2008, Li 2010). This variant has also been identified by our lab oratory in 1 Native American individual with HCM and 1 African American infant w ith DCM. This variant has been identified in 6/8600 European American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs45577134). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, the clinical significance of the Ala698Thr variant is uncertain.
GeneDx RCV000767131 SCV000236011 uncertain significance not provided 2018-12-17 criteria provided, single submitter clinical testing The A698T variant of uncertain significance in the LDB3 gene has been reported in two unrelated probands with DCM, however, one of these individuals also harbored a variant in the MYH7 gene that may have been the primary cause of that individual's cardiomyopathy (Hershberger et al., 2008). Subsequently, Li et al. (2010) identified A698T in a proband with DCM, as well as in the proband's clinically unaffected brother. As the affected individual also harbored a variant in the RBM20 gene, the contribution of the A698T variant to disease phenotype was uncertain (Li et al., 2010). The A698T variant is observed in 54/126644 (0.04%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the A698T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.
Invitae RCV000463936 SCV000545672 uncertain significance Myofibrillar myopathy, ZASP-related 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 698 of the LDB3 protein (p.Ala698Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. The LDB3 gene has multiple clinically relevant isoforms. The p.Ala698Thr variant occurs in alternate transcript NM_007078.2, which corresponds to position c.*26876G>A, in NM_001080116.1 that is the primary transcript listed in the Methods. This variant is present in population databases (rs45577134, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with dilated cardiomyopathy (DCM) (PMID: 19412328, 20590677). ClinVar contains an entry for this variant (Variation ID: 36446). 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.
Ambry Genetics RCV000617552 SCV000736138 uncertain significance Cardiovascular phenotype 2018-11-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770300 SCV000901733 uncertain significance Cardiomyopathy 2015-09-03 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000038750 SCV001159726 uncertain significance not specified 2019-05-11 criteria provided, single submitter clinical testing The LDB3 c.2107G>A; p.Ala703Thr variant (rs45577134), also known as c.2092G>A p.Ala698Thr in transcript NM_007078.2, is reported in the literature in several individuals affected with dilated cardiomyopathy (Hershberger 2008, Li 2010). However, this variant was also observed in the unaffected sibling of one affected individual (Li 2010), while a different affected individual also carried an additional missense variant in MYH7 that may have explained their phenotype (Hershberger 2008). The p.Ala703Thr variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (52/129114 alleles) in the Genome Aggregation Database and, it is reported in ClinVar (Variation ID 36446). The alanine at codon 703 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. Given the lack of clinical and functional data, the significance of the p.Ala703Thr variant is uncertain at this time. References: Hershberger RE et al. Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. Clin Transl Sci. 2008 May;1(1):21-6. Li D et al. Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy. Clin Transl Sci. 2010 Jun;3(3):90-7.
Integrated Genetics/Laboratory Corporation of America RCV000030118 SCV000052773 likely benign Primary dilated cardiomyopathy 2015-10-02 no assertion criteria provided clinical testing

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