ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.1460G>A (p.Arg487His)

gnomAD frequency: 0.00189  dbSNP: rs146265188
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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 RCV000126608 SCV000051398 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000038729 SCV000062407 likely benign not specified 2016-03-01 criteria provided, single submitter clinical testing p.Arg487His in exon 12 of LDB3: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (63/10364) of African chromoso mes by the Exome Aggregation Consortium (ExAC,; d bSNP dbSNP rs146265188).
GeneDx RCV000038729 SCV000170115 benign not specified 2013-11-08 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001085776 SCV000289618 benign Myofibrillar myopathy 4 2021-12-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619942 SCV000737210 likely benign Cardiovascular phenotype 2018-10-17 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);Other data supporting benign classification;Subpopulation frequency in support of benign classification
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852621 SCV000995325 likely benign Primary dilated cardiomyopathy 2018-02-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000038729 SCV001432040 benign not specified 2020-08-31 criteria provided, single submitter clinical testing Variant summary: LDB3 c.1460G>A (p.Arg487His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 249258 control chromosomes, predominantly at a frequency of 0.0058 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 200-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 African or African-American origin. c.1460G>A has been reported in the literature in in an African American individual affected with Dilated Cardiomyopathy (Pugh_2014) and in two infants, who suffered sudden death by an unknown cause (Methner_2016). These reports 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) / likely benign (3x). Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics, Academic Medical Center RCV000038729 SCV001919749 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000126608 SCV001954440 likely benign not provided no assertion criteria provided clinical testing

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