ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.566C>T (p.Ser189Leu) (rs45487699)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172555 SCV000051397 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038759 SCV000062437 uncertain significance not specified 2015-10-12 criteria provided, single submitter clinical testing The p.Ser189Leu variant in LDB3 has been reported in 2 individuals with HCM and 1 individual with DCM, which segregated with disease in 4 affected relatives (Va tta 2003, Theis 2006, Mook 201). It has been identified by our laboratory in 7 i ndividuals (4 with DCM, 1 with LVNC, 1 with HCM and 1 with RV dilation). Additio nally, in vitro functional studies and a mouse animal model provide some evidenc e that the p.Ser189Leu variant may impact protein function (Arimura 2009, Li 201 0). However, this variant has also been identified in 0.1% (47/65318) of Europea n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs45487699). In summary, while segregation and in vivo evidence s uggest this variant may be disease-causing, its frequency in the ExAC cohort rai ses the possibility that it is not disease causing on its own. Therefore, availa ble evidence for this variant is conflicting and its clinical significance is un certain.
Invitae RCV000234541 SCV000289626 uncertain significance Myofibrillar myopathy, ZASP-related 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 189 of the LDB3 protein (p.Ser189Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. The LDB3 gene has multiple clinically relevant isoforms. The p.Ser189Leu variant occurs in alternate transcript NM_007078.2, which corresponds to position c.321+1523C>T in NM_001080116.1, the primary transcript listed in the Methods. This variant is present in population databases (rs45487699, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported to segregate with dilated cardiomyopathy in a single family (PMID: 14662268). This variant has also been observed in individuals with hypertrophic cardiomyopathy (PMID: 17097056, 23785128) and dilated cardiomyopathy (PMID: 25163546). This variant is also known as p.Ser196Leu in the literature. ClinVar contains an entry for this variant (Variation ID: 4731). Experimental studies have shown that this missense change reduces the affinity of LDB3 to PGM1 (PMID: 19377068) and lowers the recovery rate (PMID: 24647531). Experimental studies in transgenic mice have shown that this missense change recapitulates a cardiovascular disease phenotype (PMID: 20852297). 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000172555 SCV000341972 uncertain significance not provided 2016-06-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172555 SCV000574855 likely pathogenic not provided 2016-11-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618756 SCV000736451 uncertain significance Cardiovascular phenotype 2018-05-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
OMIM RCV000004996 SCV000025172 pathogenic Dilated cardiomyopathy 1C 2006-12-29 no assertion criteria provided literature only
OMIM RCV000170300 SCV000222636 pathogenic Familial hypertrophic cardiomyopathy 24 2006-12-29 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000172555 SCV000924838 uncertain significance not provided 2017-05-30 no assertion criteria provided provider interpretation

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