Submissions for variant NM_007078.3(LDB3):c.1675C>T (p.Arg559Trp)

gnomAD frequency: 0.00008  dbSNP: rs142947567

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000545064	SCV000638686	uncertain significance	Myofibrillar myopathy 4	2023-12-02	criteria provided, single submitter	clinical testing	The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*17396C>T in the primary transcript. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 559 of the LDB3 protein (p.Arg559Trp). This variant is present in population databases (rs142947567, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31931689, 32880476). 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.
Ambry Genetics	RCV002404434	SCV002714608	uncertain significance	Cardiovascular phenotype	2022-04-15	criteria provided, single submitter	clinical testing	The p.R559W variant (also known as c.1675C>T), located in coding exon 9 of the LDB3 gene, results from a C to T substitution at nucleotide position 1675. The arginine at codon 559 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in individuals from dilated cardiomyopathy cohorts; however, details were limited (Ramchand J et al. J Am Heart Assoc, 2020 01;9:e013346; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001091336	SCV001952379	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001091336	SCV001968981	uncertain significance	not provided		no assertion criteria provided	clinical testing