ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.656G>A (p.Arg219Gln) (rs530979771)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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 2016-07-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LDB3 gene. The R219Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations, and it was not observed with any significant frequency in the 1000 Genomes Project. The R219Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000639872 SCV000761455 uncertain significance Myofibrillar myopathy, ZASP-related 2017-09-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 219 of the LDB3 protein (p.Arg219Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. The LDB3 gene has multiple clinically relevant isoforms. The p.Arg219Gln variant occurs in alternate transcript NM_001171610.1, which corresponds to position c.321+1613G>A in NM_001080116.1, the primary transcript listed in the Methods. This variant is present in population databases (rs530979771, ExAC 0.01%). This variant has not been reported in the literature in individuals with LDB3-related disease. ClinVar contains an entry for this variant (Variation ID: 179653). 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"). 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.
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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