ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.331A>G (p.Arg111Gly) (rs730881088)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159259 SCV000209205 uncertain significance not provided 2016-06-06 criteria provided, single submitter clinical testing The R111G variant of uncertain significance in the TNNI3 gene has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Two variants in nearby residues (A116G, T119N) have been reported in the Human Gene Mutation Database in association with cariomyopathy (Stenson et al., 2014); however, the pathogenicty of these variants has not been definitively determined. The R111G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, functional studies have not been performed in order to definitively determine the impact of this variant on protein structure and function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000818370 SCV000958980 uncertain significance Hypertrophic cardiomyopathy 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 111 of the TNNI3 protein (p.Arg111Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs730881088, ExAC 0.006%). This variant has not been reported in the literature in individuals with TNNI3-related disease. ClinVar contains an entry for this variant (Variation ID: 181600). 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: "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.
Color Health, Inc RCV001190439 SCV001357932 uncertain significance Cardiomyopathy 2019-06-22 criteria provided, single submitter clinical testing

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