Submissions for variant NM_007078.3(LDB3):c.536A>G (p.Asp179Gly)

gnomAD frequency: 0.00001  dbSNP: rs794729058

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183519	SCV000235979	uncertain significance	not provided	2018-06-27	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the LDB3 gene. The D179G variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The D179G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. However, this variant occurs in an alternate transcript where no nearby missense variants have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics	RCV000617757	SCV000736914	uncertain significance	Cardiovascular phenotype	2017-09-15	criteria provided, single submitter	clinical testing	The p.D179G variant (also known as c.536A>G), located in coding exon 4 of the LDB3 gene, results from an A to G substitution at nucleotide position 536. The aspartic acid at codon 179 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and glycine is the reference amino acid in other 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000183519	SCV000987568	uncertain significance	not provided		criteria provided, single submitter	clinical testing
Invitae	RCV002056959	SCV002359653	uncertain significance	Myofibrillar myopathy 4	2023-05-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 179 of the LDB3 protein (p.Asp179Gly). 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 sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 201839). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. This variant is present in population databases (rs794729058, gnomAD 0.0009%). The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.321+1493A>G in the primary transcript.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993870	SCV004812999	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing	Variant summary: LDB3 c.536A>G (p.Asp179Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249124 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.536A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 201839). Based on the evidence outlined above, the variant was classified as uncertain significance.