ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.690-4621A>G (rs370053163)

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Total submissions: 3
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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, ZASP-related 2018-09-26 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs370053163, ExAC 0.05%). This variant has not been reported in the literature in individuals with LDB3-related disease. ClinVar contains an entry for this variant (Variation ID: 518922). Nucleotide substitutions within 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 may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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