Submissions for variant NM_007078.3(LDB3):c.139G>A (p.Asp47Asn)

gnomAD frequency: 0.00001  dbSNP: rs397517212

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038725	SCV000062403	uncertain significance	not specified	2012-05-24	criteria provided, single submitter	clinical testing	The Asp47Asn variant in LDB3 has not been reported in the literature nor previou sly identified by our laboratory. This variant has not been identified in a very large and broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS). This low frequency is consistent with a disease causing ro le, but insufficient to establish this with confidence. Computational analyses ( biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Addition al information is needed to fully assess the clinical significance of the Asp47A sn variant.
Invitae	RCV000811533	SCV000951801	uncertain significance	Myofibrillar myopathy 4	2023-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 47 of the LDB3 protein (p.Asp47Asn). This variant is present in population databases (rs397517212, gnomAD 0.003%). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 33500567). ClinVar contains an entry for this variant (Variation ID: 45517). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171119	SCV001333799	uncertain significance	Cardiomyopathy	2018-10-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001588854	SCV001815347	uncertain significance	not provided	2019-09-30	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#45517; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Ambry Genetics	RCV002390160	SCV002697706	uncertain significance	Cardiovascular phenotype	2019-01-04	criteria provided, single submitter	clinical testing	The p.D47N variant (also known as c.139G>A), located in coding exon 2 of the LDB3 gene, results from a G to A substitution at nucleotide position 139. The aspartic acid at codon 47 is replaced by asparagine, an amino acid with highly 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.