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

gnomAD frequency: 0.00001  dbSNP: rs730881088

Total submissions: 7

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818370	SCV000958980	uncertain significance	Hypertrophic cardiomyopathy	2024-11-13	criteria provided, single submitter	clinical testing	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). This variant is present in population databases (rs730881088, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with TNNI3-related conditions. ClinVar contains an entry for this variant (Variation ID: 181600). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 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	2024-12-19	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 variant was reported in an individual in a left ventricular non-compaction (LVNC) cohort, but clinical details were limited (Grebur K et al. Front Cardiovasc Med, 2024 Feb;11:1337378). This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant 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
All of Us Research Program, National Institutes of Health	RCV000818370	SCV004819072	uncertain significance	Hypertrophic cardiomyopathy	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 111 of the TNNI3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/249460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786434	SCV005398800	uncertain significance	Dilated cardiomyopathy 1FF	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Gain of function and loss of function are reported mechanisms of disease in this gene. The former is associated with familial restrictive cardiomyopathy 1 (MIM#115210) and hypertrophic cardiomyopathy 7 (MIM#613690), while the latter is associated with dilated cardiomyopathy 1FF (MIM#613286) (PMIDs: 19914256, 21533915). (I) 0108 - This gene is associated with both recessive and dominant disease. The recessive form of inheritance is the exception and has only been reported in a small number of families (PMIDs: 15070570, 23270746). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 15607392). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 23270746). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (6 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated troponin domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg111Ile) has been reported as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS in multiple individuals, including an adult with DCM, two adults with HCM who harboured other pathogenic HCM/DCM variant(s), and five individuals not known to have heart disease (ClinVar, personal communication). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign