Submissions for variant NM_007078.3(LDB3):c.689+10G>A

gnomAD frequency: 0.00125  dbSNP: rs45563234

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038765	SCV000062443	benign	not specified	2017-08-23	criteria provided, single submitter	clinical testing	c.689+10G>A in intron 04 of LDB3: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence and has been identified in 0.3% (67/24532) of South Asian chromosomes, including 1 h omozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs45563234).
Invitae	RCV000231371	SCV000289628	likely benign	Myofibrillar myopathy 4	2024-01-24	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000038765	SCV000340029	likely benign	not specified	2016-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038765	SCV001426824	benign	not specified	2020-07-27	criteria provided, single submitter	clinical testing	Variant summary: LDB3 c.689+10G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/4 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 0.0013 in 254596 control chromosomes, predominantly at a frequency of 0.0028 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 112 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 South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign (1x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Athena Diagnostics	RCV000038765	SCV001476530	benign	not specified	2020-03-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001528359	SCV001943235	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001528359	SCV002048758	benign	not provided	2023-11-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496618	SCV002805150	likely benign	Dilated cardiomyopathy 1C; Myofibrillar myopathy 4	2021-08-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003964862	SCV004782019	likely benign	LDB3-related disorder	2020-11-26	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528359	SCV001739994	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038765	SCV001917641	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528359	SCV001928845	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000038765	SCV001964389	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001528359	SCV002036075	likely benign	not provided		no assertion criteria provided	clinical testing