ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.1910C>T (p.Ala637Val) (rs141569007)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767130 SCV000576483 uncertain significance not provided 2018-08-31 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LDB3 gene. The A637V variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 4/10,934 (0.04%) alleles from individuals of African ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). The A637V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, this substitution occurs at a position that is conserved across species and in silico analysis suggests that this variant is probably damaging to the protein structure/function.
Ambry Genetics RCV000619404 SCV000737061 uncertain significance Cardiovascular phenotype 2015-12-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
Invitae RCV000685509 SCV000812992 uncertain significance Myofibrillar myopathy, ZASP-related 2018-06-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 637 of the LDB3 protein (p.Ala637Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. The LDB3 gene has multiple clinically relevant transcripts. The p.Ala637Val variant occurs in alternate transcript NM_007078.2, which corresponds to position c.*19405C>T in NM_001080116.1, the primary transcript listed in the Methods. This variant is present in population databases (rs141569007, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 45536). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C65"). 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, Partners HealthCare 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).

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