Submissions for variant NM_007078.3(LDB3):c.793C>T (p.Arg265Cys)

gnomAD frequency: 0.00005  dbSNP: rs45521338

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171994	SCV000054753	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038769	SCV000062447	uncertain significance	not specified	2012-08-03	criteria provided, single submitter	clinical testing	The Arg265Cys variant in LDB3 has been identified in 0.5% (2/394) of Chinese chr omosomes from a broad population by the 1000 Genomes Project (dbSNP rs45521338) and in 1/4406 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Although detection of this variant in these populations raises the possibility that this variant ma y be benign, it cannot be ruled out that these individuals are not presymptomati c. Computational analyses (biochemical amino acid properties, conservation, Alig nGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. Addit ional information is needed to fully assess the clinical significance of this va riant.
GeneDx	RCV000171994	SCV000235995	uncertain significance	not provided	2019-05-17	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23861362, 20474083, 28821295)
Invitae	RCV000806776	SCV000946793	uncertain significance	Myofibrillar myopathy 4	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 218 of the LDB3 protein (p.Arg218Cys). This variant is present in population databases (rs45521338, gnomAD 0.08%). This missense change has been observed in individual(s) with congentital left ventricular aneurysm and left ventricular trabeculation (PMID: 28821295). This variant is also known as c.793C>T, p.Arg265Cys. ClinVar contains an entry for this variant (Variation ID: 45555). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038769	SCV001363756	likely benign	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: LDB3 c.793C>T (p.Arg265Cys) results in a non-conservative amino acid change located in the PDZ and LIM domain protein 1-4/Zasp-like, middle domain (IPR031847) of 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 0.00015 in 251420 control chromosomes, predominantly at a frequency of 0.00082 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 33-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 a benign polymorphism found primarily in populations of East Asian origin. c.793C>T has been reported in the literature in an Asian male affected with congenital left ventricular aneurysm and prominent left ventricular trabeculation (e.g. Shan_2017), in a Chinese individual affected with dilated cardiomyopathy (e.g. Shen_2022), and in a participant from a exome sequencing cohort not selected for arrhythmia, cardiomyopathy, or a family history of sudden death (e.g. Ng_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23861362, 28821295, 35284542). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as likely benign (n=1) or uncertain sinificance (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002415478	SCV002677375	likely benign	Cardiovascular phenotype	2022-04-12	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470735	SCV002768322	uncertain significance	Dilated cardiomyopathy 1C	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is the proposed mechanism of disease in this gene associated with missense variants and is associated with dilated cardiomyopathy 1C, with or without LVNC (MIM#601493), hypertrophic cardiomyopathy 24 (MIM#601493), left ventricular noncompaction 3 (MIM#601493) and myofibrillar myopathy 4 (MIM#609452) (PMID: 19377068). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (37 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (36 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated DUF4749 domain (NCBI). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change to a histidine has conflicting reports of likely benign and VUS in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as likely pathogenic in an individual with congenital left ventricular aneurysm and prominent left ventricular trabeculation (PMID: 28821295). It is also reported as VUS in another individual with cardiomyopathy (PMID: 23861362). In addition, conflicting reports of likely benign and VUS are listed in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV000171994	SCV003816514	uncertain significance	not provided	2022-01-18	criteria provided, single submitter	clinical testing