Submissions for variant NM_007078.3(LDB3):c.1381T>G (p.Tyr461Asp)

gnomAD frequency: 0.00002  dbSNP: rs145655904

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000229837	SCV000289616	uncertain significance	Myofibrillar myopathy 4	2023-11-17	criteria provided, single submitter	clinical testing	The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.2, and corresponds to NM_001080116.1:c.*17102T>G in the primary transcript. This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 461 of the LDB3 protein (p.Tyr461Asp). This variant is present in population databases (rs145655904, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. 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	RCV002379012	SCV002699840	uncertain significance	Cardiovascular phenotype	2022-03-03	criteria provided, single submitter	clinical testing	The p.Y461D variant (also known as c.1381T>G), located in coding exon 9 of the LDB3 gene, results from a T to G substitution at nucleotide position 1381. The tyrosine at codon 461 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This amino acid position is conserved. 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.
GeneDx	RCV000786157	SCV002759086	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Reported using an alternate transcript of the gene; In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786157	SCV000924840	uncertain significance	not provided	2016-06-21	no assertion criteria provided	provider interpretation	Gene-level evidence for LDB3 and LVNC There is limited evidence linking the LDB3 gene to LVNC. Vatta et al., 2003 reported LDB3 variants via candidate gene screening in 6 of 100 probands with a DCM, DCM/LVNC, and LVNC spectrum of phenotypes. We have seen this variant in one individual with LVNC. Testing was done through Invitae. Given the lack of case data we consider this variant to be of unknown significance and we do not currently feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). However, this variant is of interest, as it is located in an exon that is preferentially expressed in the heart and has been reported to be involved in other cases of cardiomyopathy. Tyr461Asp There is no case data for this variant. It has not been published as a disease-causing variant in LVNC, or other cardiomyopathies or phenotypes. Invitae reports that in silico analyses (SIFT, PolyPhen-2, Align-GVD) predict this variant to be disruptive. Mutation Taster predicted it to be a polymorphism. The Tyrosine at codon 461 is not well conserved across species, though there are large physicochemical difference between tyrosine and asparagine. The variant was reported online in 1 of of 59,814 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 3/2016). Specifically, the variant was observed in 1 of 5,094 African individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).