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

gnomAD frequency: 0.00189  dbSNP: rs146265188

Total submissions: 10

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, http://exac.broadinstitute.org; 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	2024-01-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619942	SCV000737210	likely benign	Cardiovascular phenotype	2018-10-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
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.
Fulgent Genetics, Fulgent Genetics	RCV002496616	SCV002806088	likely benign	Dilated cardiomyopathy 1C; Myofibrillar myopathy 4	2021-10-20	criteria provided, single submitter	clinical testing
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