ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.793C>T (p.Arg265Cys) (rs45521338)

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Total submissions: 5
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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 RCV000171994 SCV000054753 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare 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 ( 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 2018-11-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LDB3 gene. The R265C variant has been reported in a patient with congenital left ventricular aneurysm and prominent left ventricular trabeculation (Shan et al., 2017). This variant has also been reported in one individual from a cohort of individuals who underwent exome sequencing and were not selected for a history of cardiomyopathy, arrhythmia or family history of sudden cardiac death (Ng et al., 2013). The R265C variant is observed in 13/17248 (0.075%) alleles from individuals of East Asian ancestry and in 18/33582 (0.054%) alleles from individuals of Latino ancestry in large population cohorts (Lek et al., 2016). Nevertheless, the R265C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000806776 SCV000946793 uncertain significance Myofibrillar myopathy, ZASP-related 2020-09-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 218 of the LDB3 protein (p.Arg218Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs45521338, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with congentital left ventricular aneurysm and left ventricular trabeculation (PMID: 28821295). This variant is also known as c.793C>T, p.Arg265Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 45555). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C2). 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. 5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000038769 SCV001363756 likely benign not specified 2019-05-06 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 domain of unknown function DUF4749 (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 (Shan_2017) and also in a participant from a exome sequencing cohort not selected for arrhythmia, cardiomyopathy, or a family history of sudden death (Ng_2013). These reports however, 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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