Submissions for variant NM_000363.5(TNNI3):c.421C>G (p.Arg141Gly)

dbSNP: rs730881071

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001178726	SCV001343238	uncertain significance	Cardiomyopathy	2019-08-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 141 of the TNNI3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant 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. This variant has been reported in an individual referred for cardiomyopathy test, who showed no left ventricular hypertrophy (PMID: 24704860). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg141Gln, is associated with disease (Clinvar variation ID 43381), suggesting that arginine at this position is important for the protein function. 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	RCV002327433	SCV002630741	uncertain significance	Cardiovascular phenotype	2019-12-20	criteria provided, single submitter	clinical testing	The p.R141G variant (also known as c.421C>G), located in coding exon 7 of the TNNI3 gene, results from a C to G substitution at nucleotide position 421. The arginine at codon 141 is replaced by glycine, an amino acid with dissimilar properties. A different alteration located at the same position, p.R141Q, has been detected in several individuals with hypertrophic cardiomyopathy (HCM) (Richard P et al. Circulation. 2003;107:2227-32; Van Driest SL et al. Circulation. 2003;108:445-51; van den Wijngaard A et al. Neth Heart J. 2011;19:344-51; Rani DS et al. BMC Med. Genet. 2012;13:69; Zou Y et al. Mol Biol Rep. 2013;40:3969-76; Landry CH et al. N Engl J Med. 2017;377(20):1943-1953; Curila K et al. Genet Test Mol Biomarkers. 2009;13:647-50), was detected in the homozygous state in an individual with severe biventricular hypertrophy (Mogensen J et al. J Am Coll Cardiol. 2004;44:2315-25), has co-occurred with other variants in cardiac-related genes in affected individuals (Morita H et al. N Engl J Med. 2008;358:1899-908; Santos S et al. BMC Med Genet. 2012;13:17), and has been detected in unaffected relatives (Mogensen J et al. J Am Coll Cardiol. 2004;44:2315-25). In addition, a different alteration located at the same position, p.R141W, has been detected in one individual with hypertrophic cardiomyopathy (HCM) (Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of the p.R141G alteration remains unclear.
Invitae	RCV002555493	SCV003323188	uncertain significance	Hypertrophic cardiomyopathy	2023-06-17	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Arg141 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707239, 18403758, 19645627, 23283745). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 920147). This variant has not been reported in the literature in individuals affected with TNNI3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 141 of the TNNI3 protein (p.Arg141Gly).