Submissions for variant NM_007078.3(LDB3):c.2174T>A (p.Ile725Asn)

gnomAD frequency: 0.00004  dbSNP: rs748399477

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000639861	SCV000761444	uncertain significance	Myofibrillar myopathy 4	2024-01-08	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.*33592T>A in the primary transcript. This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 725 of the LDB3 protein (p.Ile725Asn). This variant is present in population databases (rs748399477, gnomAD 0.006%). This missense change has been observed in individual(s) with left ventricular noncompaction, dilated cardiomyopathy, or limb-girdle muscular dystrophy (PMID: 25214167, 28798025, 32880476). This variant is also known as p.I615N, p.I725N. ClinVar contains an entry for this variant (Variation ID: 532921). 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196106	SCV001366577	uncertain significance	Dilated cardiomyopathy 1C	2019-06-21	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP5.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798937	SCV002043379	uncertain significance	Cardiomyopathy	2021-04-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002424426	SCV002730567	uncertain significance	Cardiovascular phenotype	2022-08-02	criteria provided, single submitter	clinical testing	The p.I725N variant (also known as c.2174T>A), located in coding exon 13 of the LDB3 gene, results from a T to A substitution at nucleotide position 2174. The isoleucine at codon 725 is replaced by asparagine, an amino acid with dissimilar properties. This alteration has been reported in a myopathy cohort, as well as a left ventricular non-compaction (LVNC) cohort; however, clinical details were limited in both cases (Savarese M et al. Acta Neuropathol Commun, 2014 Sep;2:100; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:[ePub ahead of print]). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003327436	SCV004034381	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	Identified in patients with LVNC and DCM in published literature (Miszalski-Jamka et al., 2017; Verdonschot et al., 2020); multiple patients harbored additional cardiogenetic variants; Reported in association with limb-girdle muscular dystrophy (LGMD) (Savarese et al., 2014); 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: 32880476, 28798025, 25214167)