ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.656G>A (p.Arg219Gln)

gnomAD frequency: 0.00002  dbSNP: rs530979771
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000156449 SCV000206168 uncertain significance not specified 2014-04-04 criteria provided, single submitter clinical testing The Arg219Gln variant in LDB3 has not been previously reported in individuals wi th cardiomyopathy or in large population studies. Computational prediction tools and conservation analysis suggest that the Arg219Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogeni city. Additional information is needed to fully assess the clinical significance of the Arg219Gln variant.
GeneDx RCV000767016 SCV000565702 uncertain significance not provided 2020-01-16 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 179653; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Invitae RCV000639872 SCV000761455 uncertain significance Myofibrillar myopathy 4 2024-01-15 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.321+1613G>A in the primary transcript. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 219 of the LDB3 protein (p.Arg219Gln). This variant is present in population databases (rs530979771, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 179653). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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 RCV002362830 SCV002665975 uncertain significance Cardiovascular phenotype 2018-07-17 criteria provided, single submitter clinical testing The p.R219Q variant (also known as c.656G>A), located in coding exon 4 of the LDB3 gene, results from a G to A substitution at nucleotide position 656. The arginine at codon 219 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in an individual with idiopathic restrictive cardiomyopathy, who also had additional cardiac variants detected (Kostareva A et al. PLoS ONE Sep;11:e0163362). This amino acid position is well conserved in available 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000767016 SCV000924837 uncertain significance not provided 2017-10-30 no assertion criteria provided provider interpretation p.Arg219Gln (R219Q; c.656G>A) in exon 4 of the LDB3 gene (alternative transcript NM_001171610.1) Chromosome position 10:88441527 G / A Based on the information reviewed below, we classify this as a Variant of Uncertain Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. It does not look particularly suspicious to cause disease, given that it has not been convincingly reported to cause disease in a patient, and also given how variable this codon is across species. This variant has not previously been reported in the literature in association with disease. It is present in population databases. This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Glutamine. Arginine at this location is poorly conserved across ~100 vertebrate species for which we have data. It is frequently replaced by a positively-charged Lysine or a polar Asparagine, among other amino acids. Adjacent amino acids are also poorly conserved. There are no convincingly Likely Pathogenic or Pathogenic missense variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably damaging"; Align-GVGD: "Class C0"). This variant was reported in 7 individuals with European ancestry in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 6 non-Finnish Europeans (for the highest minor allele frequency: 0.006%), and 1 Finnish European. Overall MAF = 0.003%. 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. The curators made an effort to exclude individuals with severe pediatric diseases.

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