ClinVar Genomic variation as it relates to human health

Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in the published literature (PMID: 29121657, 30847666); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 32758068, 29121657)

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TNNI3 related disorder (ClinVar ID: VCV000181580). A different missense change at the same codon (p.Arg141Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043381). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 141 of the TNNI3 protein (p.Arg141Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with TNNI3-related conditions (PMID: 29121657, 30847666, 32758068). ClinVar contains an entry for this variant (Variation ID: 181580). 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. 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, 15607392, 18403758, 19645627, 22429680, 22876777, 23283745, 25524337). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 missense variant replaces arginine with tryptophan at codon 141 of the TNNI3 protein. Computational prediction suggests that this variant may have 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 been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 29121657). This variant has been identified in 2/248702 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg141Gln, has been associated with hypertrophic cardiomyopathy (Clinvar variation ID: 43381), suggesting that arginine at this position is important for the protein function. 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.

The p.R141W variant (also known as c.421C>T), located in coding exon 7 of the TNNI3 gene, results from a C to T substitution at nucleotide position 421. The arginine at codon 141 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected in one individual with hypertrophic cardiomyopathy (HCM) and in a genetic testing cohort with limited clinical details (Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). In addition, 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). This amino acid position is well conserved in available vertebrate species. 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 the p.R141W alteration remains unclear.