Submissions for variant NM_007078.3(LDB3):c.690-4621A>G

gnomAD frequency: 0.00016  dbSNP: rs370053163

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000620240	SCV000736612	uncertain significance	Cardiovascular phenotype	2016-06-03	criteria provided, single submitter	clinical testing	The c.548+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 5 in the LDB3 gene. Based on data from the Exome Aggregation Consortium (ExAC), the G allele has an overall frequency of less than 0.01% (5/120456 alleles). The highest observed frequency was 0.05% (5/8478) in the African subpopulation. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.02% (2/12810 total alleles), having been observed in 0.05% (2/4308) African American alleles. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, BDGP shows this alteration does not have any significant effect on the native donor splice site and ESEfinder shows this alteration is predicted to slightly weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae	RCV000808675	SCV000948789	uncertain significance	Myofibrillar myopathy 4	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the LDB3 gene. It does not directly change the encoded amino acid sequence of the LDB3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs370053163, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 518922). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
GeneDx	RCV001560671	SCV001783128	uncertain significance	not provided	2021-04-02	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 518922; Landrum et al., 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Clinical Genetics, Academic Medical Center	RCV001560671	SCV001925331	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001560671	SCV001970098	likely benign	not provided		no assertion criteria provided	clinical testing