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

gnomAD frequency: 0.00049  dbSNP: rs45487699

Total submissions: 13

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, Mass General Brigham 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 4	2024-01-29	criteria provided, single submitter	clinical testing	The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.321+1523C>T in the primary transcript. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 189 of the LDB3 protein (p.Ser189Leu). This variant is present in population databases (rs45487699, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic or dilated cardiomyopathy and sudden cardiac death (PMID: 17097056, 23785128, 25163546, 25351510, 35087879). This variant is also known as p.Ser196Leu. ClinVar contains an entry for this variant (Variation ID: 4731). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects LDB3 function (PMID: 19377068, 20852297, 24647531). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Eurofins Ntd Llc (ga)	RCV000172555	SCV000341972	uncertain significance	not provided	2016-06-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172555	SCV000574855	uncertain significance	not provided	2022-05-01	criteria provided, single submitter	clinical testing	LDB3: PM1, PP1, PP2, PS3:Supporting, BP4
Ambry Genetics	RCV000618756	SCV000736451	likely benign	Cardiovascular phenotype	2022-09-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
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	RCV000172555	SCV001472987	uncertain significance	not provided	2023-09-25	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 individuals affected with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy, or ventricular tachycardia (Haas 2014, Khan 2022, Leinonen 2018, Mook 2013, Theis 2006), including one family with four affected relatives (Vatta 2003). This variant is also reported in an individual affected with left ventricular noncompaction (LVNC) with an alternate molecular explanation for disease (Mazzarotto 2021). 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 also reported in ClinVar (Variation ID: 4731) and is found in the general population with an allele frequency of 0.062% (173/281,154 alleles) in the Genome Aggregation Database (v2.1.1), which is higher than expected for a pathogenic variant in LDB3. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.183). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Arimura et al. Impaired Binding of ZASP/Cypher With Phosphoglucomutase 1 Is Associated With Dilated Cardiomyopathy. Cardiovasc Res. 2009 Jul 1;83(1):80-8. PMID: 19377068. Haas et al. Atlas of the Clinical Genetics of Human Dilated Cardiomyopathy. Eur Heart J. 2015 May 7;36(18):1123-35a. PMID: 25163546. Khan RS et al. Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy. J Am Heart Assoc. 2022 Jan 4;11(1):e022854. PMID: 34935411. Leinonen et al. The Genetics Underlying Idiopathic Ventricular Fibrillation: A Special Role for Catecholaminergic Polymorphic Ventricular Tachycardia? Int J Cardiol. 2018 Jan 1;250:139-145. PMID: 29032884. Li et al. A ZASP Missense Mutation, S196L, Leads to Cytoskeletal and Electrical Abnormalities in a Mouse Model of Cardiomyopathy. Circ Arrhythm Electrophysiol. 2010 Dec;3(6):646-56. PMID: 20852297. Mazzarotto F et al. Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies. Genet Med. 2021 May;23(5):856-864. PMID: 33500567. Mook et al. Targeted Sequence Capture and GS-FLX Titanium Sequencing of 23 Hypertrophic and Dilated Cardiomyopathy Genes: Implementation Into Diagnostics. J Med Genet. 2013 Sep;50(9):614-26. PMID: 23785128. Theis et al. Echocardiographic-determined Septal Morphology in Z-disc Hypertrophic Cardiomyopathy. Biochem Biophys Res Commun. 2006 Dec 29;351(4):896-902. PMID: 17097056. Vatta et al. Mutations in Cypher/ZASP in Patients With Dilated Cardiomyopathy and Left Ventricular Non-Compaction. J Am Coll Cardiol. 2003 Dec 3;42(11):2014-27. PMID: 14662268.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001797992	SCV002043384	uncertain significance	Cardiomyopathy	2020-03-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038759	SCV003933870	uncertain significance	not specified	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: LDB3 c.566C>T (p.Ser189Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 249768 control chromosomes. The observed variant frequency is approximately 25.94 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.566C>T has been reported in the literature in individuals affected with DCM, including 4 affected members of a family (examples: Vatta_2003, Khan_2022. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Experimental evidence has shown the variant to impact protein function (example: Arimura_2009) and mice that expressed the variant developed hemodynamic dysfunction consistent with DCM (Li_2010). The following publications have been ascertained in the context of this evaluation (PMID: 19377068, 34935411, 20852297, 14662268). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Eight submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as VUS.
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