rs727503130
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.
The NM_007078.3(LDB3):c.1786G>A(p.Val596Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_007078.3 missense
Scores
Clinical Significance
Conservation
Publications
- myofibrillar myopathy 4Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- familial dilated cardiomyopathyInheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000199 AC: 5AN: 251492 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 727234 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Uncertain:1
The p.Val596Ile variant in LDB3 has been identified by our laboratory in 1 Hispa nic infant with CHD and coarctation of the aorta. It has also been identified in 3/66734 European chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org). Computational prediction tools and conservation analys is suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signi ficance of the p.Val596Ile variant is uncertain. -
Myofibrillar myopathy 4 Uncertain:1
The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*18699G>A in the primary transcript. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 596 of the LDB3 protein (p.Val596Ile). This variant is present in population databases (rs727503130, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. 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. -
not provided Uncertain:1
The LDB3 c.1786G>A; p.Val596Ile variant (rs727503130) is reported in the literature in an individual with non-ischemic cardiomyopathy, although its clinical significance was not demonstrated (Vokac 2024). This variant is found in the non-Finnish European population with an allele frequency of 0.004% (5/113,766 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.405). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Vokac D et al. The Role of Next-Generation Sequencing in the Management of Patients with Suspected Non-Ischemic Cardiomyopathy after Syncope or Termination of Sudden Arrhythmic Death. Genes (Basel). 2024 Jan 5;15(1):72. PMID: 38254962. -
Cardiovascular phenotype Uncertain:1
The p.V596I variant (also known as c.1786G>A), located in coding exon 10 of the LDB3 gene, results from a G to A substitution at nucleotide position 1786. The valine at codon 596 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at