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

gnomAD frequency: 0.00001  dbSNP: rs730881088

Total submissions: 5

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	2022-06-25	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 181600). This variant has not been reported in the literature in individuals affected with TNNI3-related conditions. This variant is present in population databases (rs730881088, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 111 of the TNNI3 protein (p.Arg111Gly). 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. 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").
Color Diagnostics, LLC DBA Color Health	RCV001190439	SCV001357932	uncertain significance	Cardiomyopathy	2023-10-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 111 of the TNNI3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TNNI3-related disorders in the literature. This variant has been identified in 6/249460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002453557	SCV002611624	uncertain significance	Cardiovascular phenotype	2022-01-26	criteria provided, single submitter	clinical testing	The p.R111G variant (also known as c.331A>G), located in coding exon 6 of the TNNI3 gene, results from an A to G substitution at nucleotide position 331. The arginine at codon 111 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001190439	SCV004239771	uncertain significance	Cardiomyopathy	2023-03-23	criteria provided, single submitter	clinical testing