Submissions for variant NM_007078.3(LDB3):c.1487T>C (p.Phe496Ser)

gnomAD frequency: 0.00009  dbSNP: rs147072071

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183536	SCV000236003	uncertain significance	not provided	2023-07-11	criteria provided, single submitter	clinical testing	Identified in patients with sudden unexplained death and dilated cardiomyopathy in the published literature; described as Phe386Ser, Phe496Ser, and Phe501Ser using various alternate transcripts (Lin et al., 2017; van Lint et al., 2019; Burstein et al., 2021; Iglesias et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 33919104, 32746448, 29247119, 30847666)
Invitae	RCV000532739	SCV000638685	uncertain significance	Myofibrillar myopathy 4	2023-11-18	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.*17208T>C in the primary transcript. This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 496 of the LDB3 protein (p.Phe496Ser). This variant is present in population databases (rs147072071, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of LDB3-related conditions (PMID: 29247119, 30847666, 32746448). This variant is also known as c.180T>C (p.Phe386Ser). ClinVar contains an entry for this variant (Variation ID: 201849). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845399	SCV000987463	uncertain significance	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390470	SCV002698592	uncertain significance	Cardiovascular phenotype	2021-04-07	criteria provided, single submitter	clinical testing	The p.F496S variant (also known as c.1487T>C), located in coding exon 9 of the LDB3 gene, results from a T to C substitution at nucleotide position 1487. The phenylalanine at codon 496 is replaced by serine, an amino acid with highly dissimilar properties. This variant (also described as p.F386S) has been reported in a sudden unexplained death case and a dilated cardiomyopathy genetic testing case; however, clinical details were limited for both individuals (Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:[Epub ahead of print]; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309).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, Fulgent Genetics	RCV002503718	SCV002816556	uncertain significance	Dilated cardiomyopathy 1C; Myofibrillar myopathy 4	2021-11-09	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000183536	SCV001918193	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000183536	SCV001976324	uncertain significance	not provided		no assertion criteria provided	clinical testing