Submissions for variant NM_007078.3(LDB3):c.1910C>T (p.Ala637Val)

gnomAD frequency: 0.00018  dbSNP: rs141569007

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767130	SCV000576483	likely benign	not provided	2019-05-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27532257, 24503780)
Ambry Genetics	RCV000619404	SCV000737061	uncertain significance	Cardiovascular phenotype	2022-11-29	criteria provided, single submitter	clinical testing	The p.A637V variant (also known as c.1910C>T), located in coding exon 11 of the LDB3 gene, results from a C to T substitution at nucleotide position 1910. The alanine at codon 637 is replaced by valine, an amino acid with similar properties. This variant has been reported in an individual with dilated cardiomyopathy (Pugh et al. Genet Med. 2014;16(8):601-8). This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685509	SCV000812992	uncertain significance	Myofibrillar myopathy 4	2024-01-26	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.*19405C>T in the primary transcript. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 637 of the LDB3 protein (p.Ala637Val). This variant is present in population databases (rs141569007, gnomAD 0.05%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 45536). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038746	SCV000062424	uncertain significance	not specified	2008-06-18	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000038746	SCV000280176	uncertain significance	not specified	2013-07-31	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LDB3 p.Ala637Val Given the lack of case data, we consider this a variant of uncertain significance. We could find no reports of the variant in association with disease. In silico analysis predicts the variant to be probably damaging, per the GeneDx report. The alanine at codon 637 is conserved across species. The variant was reported online in 8 of 60,661 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 February 17th, 2015). Specifically, the variant was observed in 4 of 5,197 Africans, 2/8255 South Asians, 1/5,789 Latinos, 1/33,336 Europeans. 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).