Submissions for variant NM_007078.3(LDB3):c.1014A>G (p.Thr338=)

gnomAD frequency: 0.00450  dbSNP: rs150209221

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038714	SCV000062392	benign	not specified	2012-04-11	criteria provided, single submitter	clinical testing	Thr338Thr in Exon 10 of LDB3: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 1.2% (43/3736) of Afric an American chromosomes from a broad population by the NHLBI Exome Sequencing Pr oject (http://evs.gs.washington.edu/EVS; dbSNP rs150209221).
PreventionGenetics, part of Exact Sciences	RCV003891483	SCV000311687	benign	LDB3-related condition	2023-05-22	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Invitae	RCV001085854	SCV000557550	benign	Myofibrillar myopathy 4	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620086	SCV000736317	benign	Cardiovascular phenotype	2016-09-23	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Athena Diagnostics Inc	RCV000712208	SCV000842646	benign	not provided	2018-03-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769283	SCV000900661	benign	Cardiomyopathy	2016-07-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038714	SCV000917574	benign	not specified	2018-08-06	criteria provided, single submitter	clinical testing	Variant summary: LDB3 c.1014A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0014 in 276194 control chromosomes, predominantly at a frequency of 0.015 within the African subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 600-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 origin. To our knowledge, no occurrence of c.1014A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000712208	SCV001939651	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000712208	SCV002544443	benign	not provided	2022-04-01	criteria provided, single submitter	clinical testing	LDB3: BS1, BS2