10-86716377-CCCTACACCCCCTCCCCTGCCCCTGCCTACACCCCCTCCCCTGCCCCTG-CCCTACACCCCCTCCCCTGCCCCTG
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4BP6
The NM_007078.3(LDB3):c.1320_1343delCCCTGCCCCTGCCTACACCCCCTC(p.Pro441_Ser448del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000087 ( 0 hom., cov: 26)
Exomes 𝑓: 0.000093 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
LDB3
NM_007078.3 disruptive_inframe_deletion
NM_007078.3 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.40
Genes affected
LDB3 (HGNC:15710): (LIM domain binding 3) This gene encodes a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. The protein encoded by this gene interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family. Mutations in this gene have been associated with myofibrillar myopathy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been identified; all isoforms have N-terminal PDZ domains while only longer isoforms (1, 2 and 5) have C-terminal LIM domains. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_007078.3.
BP6
Variant 10-86716377-CCCTACACCCCCTCCCCTGCCCCTG-C is Benign according to our data. Variant chr10-86716377-CCCTACACCCCCTCCCCTGCCCCTG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45514.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}. Variant chr10-86716377-CCCTACACCCCCTCCCCTGCCCCTG-C is described in Lovd as [Likely_benign]. Variant chr10-86716377-CCCTACACCCCCTCCCCTGCCCCTG-C is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00 AC: 13AN: 149868Hom.: 0 Cov.: 26 FAILED QC
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GnomAD3 exomes AF: 0.000114 AC: 28AN: 244960Hom.: 0 AF XY: 0.0000826 AC XY: 11AN XY: 133132
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000932 AC: 136AN: 1458552Hom.: 0 AF XY: 0.0000923 AC XY: 67AN XY: 725534
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GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000867 AC: 13AN: 149976Hom.: 0 Cov.: 26 AF XY: 0.0000820 AC XY: 6AN XY: 73172
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jun 06, 2016 | c.1320_1343del (p.Ala442_Pro449del) in LDB3 Given the lack of case data and location of the in-frame deletion in a region of repetitive sequence within the gene, we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 1 unrelated case of DCM (not including this patient's family). We have seen the variant in a patient with DCM and a very likely pathogenic LMNA variant. Testing was done by Invitae. Pugh et al., 2014 reported the variant in an individual with DCM. The Invitae report notes, "This sequence change deletes 24 nucleotides from exon 9 of the LDB3 mRNA (c.1320_1343del). This leads to the deletion of 8 amino acid residue(s) in the LDB3 protein (p.Ala442_Pro449del) but otherwise preserves the integrity of the reading frame...The functional effect of in-frame deletions in LDB3 is unknown." This variant is absent from ExAC, the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6/6/2016). The mean coverage at that site in ExAC is 16x to ~20x. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 05, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 11, 2012 | The 1320_1343del variant (LDB3) has not been reported in the literature nor prev iously identified by our laboratory. However, one individual with DCM was found to have a duplication of the same region. This variant causes an in-frame dele tion of 8 amino acids and is within a region of repeating sequence within the LD B3 gene. This may make this region prone to deletions and duplication, but it r emains unclear whether an increased or decreased number of repeats impacts the p rotein. In summary, additional information is needed to fully assess the clinic al significance of the 1320_1343del variant. - |
Myofibrillar myopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2025 | The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*17041_*17064del in the primary transcript. This variant, c.1320_1343del, results in the deletion of 8 amino acid(s) of the LDB3 protein (p.Ala442_Pro449del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257). ClinVar contains an entry for this variant (Variation ID: 45514). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2018 | 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. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at