ClinVar Miner

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

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Total submissions: 11
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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; 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 2020-10-30 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 the two amino acids. The LDB3 gene has multiple clinically relevant isoforms. The p.Ser189Leu variant occurs in alternate transcript NM_007078.2, and corresponds to NM_001080116.1:c.321+1523C>T in the primary transcript. 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 observed in individuals affected with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 17097056, 23785128, 14662268, 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 2020-07-28 criteria provided, single submitter clinical testing The p.S189L variant (also known as c.566C>T), located in coding exon 4 of the LDB3 gene, results from a C to T substitution at nucleotide position 566. The serine at codon 189 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (Theis JL, Biochem. Biophys. Res. Commun. 2006 Dec; 351(4):896-902; Mook OR, J. Med. Genet. 2013 Sep; 50(9):614-26; Lopes LR, Heart 2015 Feb; 101(4):294-301), as well as in a family with dilated cardiomyopathy where one family member also had a trabeculated left ventricle (Vatta M, J. Am. Coll. Cardiol. 2003 Dec; 42(11):2014-27). This alteration has also been reported as a secondary cardiac variant in an exome cohort and in an idiopathic ventricular fibrillation cohort; however clinical details were limited (Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46; Leinonen JT et al. Int. J. Cardiol., 2018 Jan;250:139-145). Limited functional studies suggest this alteration may modestly impact protein function (Arimura T, Cardiovasc. Res. 2009 Jul; 83(1):80-8; Martinelli VC et al. PLoS ONE, 2014 Mar;9:e92259). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256801 SCV001433253 uncertain significance Dilated cardiomyopathy 1A 2020-01-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286422 SCV001472987 uncertain significance none provided 2020-05-28 criteria provided, single submitter clinical testing The LDB3 c.566C>T; p.Ser189Leu variant (rs45487699), also known as S196L in the literature, is reported in two probands affected with dilated cardiomyopathy (DCM), three with hypertrophic cardiomyopathy, and one with ventricular tachycardia (Haas 2014, Leinonen 2018, Mook 2013, Theis 2006, and Vatta 2003). This variant segregated with DCM in four affected relatives of one of the probands with DCM. Functional studies suggest that the p.Ser189Leu variant alters activity of the protein encoded by LDB3, and a mouse model expressing this variant protein in cardiac tissue developed DCM (Arimura 2009 and Li 2010). This variant is reported in ClinVar (Variation ID: 4731) and is found in the general population with an allele frequency of 0.061% (173/281,154 alleles) in the Genome Aggregation Database, which is higher than expected for a pathogenic variant. The serine at codon 189 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to conflicting information, the clinical significance of this variant is uncertain at this time.
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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