Submissions for variant NM_007078.3(LDB3):c.1676G>A (p.Arg559Gln)

gnomAD frequency: 0.00008  dbSNP: rs763908636

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000553122	SCV000638687	uncertain significance	Myofibrillar myopathy 4	2024-01-14	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.*17397G>A in the primary transcript. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 559 of the LDB3 protein (p.Arg559Gln). This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. This variant is present in population databases (rs763908636, gnomAD 0.02%). This missense change has been observed in individual(s) with sudden unexpected death in infancy (PMID: 26350513). ClinVar contains an entry for this variant (Variation ID: 464285). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770298	SCV000901730	uncertain significance	Cardiomyopathy	2015-11-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001331687	SCV001523783	uncertain significance	Dilated cardiomyopathy 1C	2019-11-04	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001560051	SCV001782385	uncertain significance	not provided	2022-03-17	criteria provided, single submitter	clinical testing	Apparently de novo variant (denoted as c.1691G>A (R564Q) due to the use of a different alternate transcript) in a patient with sudden infant death syndrome (SIDS) (Hertz et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26350513)
Ambry Genetics	RCV002404435	SCV002712787	uncertain significance	Cardiovascular phenotype	2021-12-22	criteria provided, single submitter	clinical testing	The p.R559Q variant (also known as c.1676G>A), located in coding exon 9 of the LDB3 gene, results from a G to A substitution at nucleotide position 1676. The amino acid change results in arginine to glutamine at codon 559, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. This variant was reported (as NM_001171610.1:c.1691G>A) in a sudden infant death case; however, clinical details were limited (Hertz CL et al. Eur. J. Hum. Genet., 2016 06;24:817-22). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. This amino acid position is highly conserved in available vertebrate species. In addition, the BayesDel in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002476148	SCV002776839	uncertain significance	Dilated cardiomyopathy 1C; Myofibrillar myopathy 4	2021-10-05	criteria provided, single submitter	clinical testing