Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000457299 | SCV000545671 | uncertain significance | Myofibrillar myopathy 4 | 2016-08-31 | criteria provided, single submitter | clinical testing | In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is present in population databases (rs746183666, ExAC 0.01%) but has not been reported in the literature in individuals with a LDB3-related disease. This sequence change replaces threonine with asparagine at codon 435 of the LDB3 protein (p.Thr435Asn). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and asparagine. The LDB3 gene has multiple clinically relevant isoforms. The p.Thr435Asn variant occurs in alternate transcript NM_001171610.1, which corresponds to position c.*17010C>A in NM_001080116.1, the primary transcript listed in the Methods. |
| ARUP Laboratories, |
RCV001002469 | SCV001160416 | uncertain significance | not specified | 2019-04-01 | criteria provided, single submitter | clinical testing | The p.Thr435Asn variant (rs746183666) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall frequency of 0.01 percent in the African population (identified on 3 out of 23,778 chromosomes) and has been reported to the ClinVar database (Variation ID: 406798). The threonine at position 435 is highly conserved and computational analyses of the effects of the p.Thr435Asn variant on protein structure and function is neutral (SIFT: tolerated, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Thr435Asn variant with certainty. |
| Ambry Genetics | RCV002379434 | SCV002689481 | uncertain significance | Cardiovascular phenotype | 2021-03-02 | criteria provided, single submitter | clinical testing | The p.T430N variant (also known as c.1289C>A), located in coding exon 9 of the LDB3 gene, results from a C to A substitution at nucleotide position 1289. The threonine at codon 430 is replaced by asparagine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002481408 | SCV002786917 | uncertain significance | Dilated cardiomyopathy 1C; Myofibrillar myopathy 4 | 2021-07-09 | criteria provided, single submitter | clinical testing |