ClinVar Genomic variation as it relates to human health

Described as mosaic in an individual with restrictive cardiomyopathy who also harbored a second missense variant in the TNNI3 gene (van den Wijngaard et al., 2011); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies demonstrated that R145Q results in a large increase in the Ca2+ sensitivity of cardiac muscle contraction (Takahashi-Yanaga et al., 2001); Reported in ClinVar (ClinVar Variant ID# 43384; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27532257, 25132132, 21533915, 23283745, 15961398, 15607392, 24111713, 29203298, 28193612, 9241277, 16288990, 31513939, 31737537, 33673806, 32686758, 34137518, 11735257)

ACMG score likely pathogenic

The p.R145Q variant (also known as c.434G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 434. The arginine at codon 145 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM), although in some cases it co-occurred with alterations in TNNI3 or other cardiac-related genes (Kimura A et al. Nat Genet. 1997;16:379-82; Mogensen J et al. J Am Coll Cardiol. 2004;44:2315-25; van den Wijngaard A et al. Neth Heart J. 2011;19:344-51; Zou Y et al. Mol Biol Rep. 2013;40:3969-76; Berge KE et al. Clin Genet. 2014;86:355-60; Wang J et al. Eur J Heart Fail. 2014;16:950-7; Kim HY et al. J Clin Med, 2020 Jun;9:[Epub ahead of print]). This variant was reported to co-segregate with disease in two families, including one family with a pair of apparently homozygous affected siblings (Robyns T et al. Eur J Hum Genet, 2017 12;25:1313-1323; Al-Shafai KN et al. Mol Genet Genomic Med, 2021 Jul;9:e1709). In vitro functional studies indicate this alteration results in reduced intrinsic inhibitory activity, increased calcium sensitivity of myofibrillar ATPase activity and increased force generation of skinned muscle fibers (Takahashi-Yanaga F et al. J Mol Cell Cardiol. 2001;33:2095-107). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is expected to be causative of autosomal dominant TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is unclear.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 145 of the TNNI3 protein (p.Arg145Gln). This variant is present in population databases (rs397516349, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy (HCM) (PMID: 9241277, 15607392, 23283745, 24111713, 25132132). ClinVar contains an entry for this variant (Variation ID: 43384). An algorithm developed specifically for the TNNI3 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). Experimental studies have shown that this missense change affects TNNI3 function (PMID: 11735257). This variant disrupts the p.Arg145 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11735257, 20641121, 23610579). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.

This missense variant replaces arginine with glutamine at codon 145 in the actin binding region 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). An experimental functional study has shown that this variant reduces the intrinsic inhibitory activity of the cardiac troponin I protein without changing the apparent affinity for actin and increases the Ca2+ sensitivity of cardiac muscle contraction (PMID: 11735257). This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 15607392, 23283745, 24111713, 25132132, 27532257, 28193612, 29255176, 32492895, 32686758, 34137518). In one family, it has been shown that this variant segregates with disease in three individuals affected with hypertrophic cardiomyopathy (PMID: 29255176). This variant has also been reported in individuals suspected to be affected with hypertrophic cardiomyopathy (PMID: 31737537, 33673806) and in an individual affected with restrictive cardiomyopathy (PMID: 21533915). This variant has been identified in 4/248984 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg145Trp and p.Arg145Gly, are considered to be disease-causing (ClinVar variation ID: 12426 and 12419), suggesting that arginine at this position is important for TNNI3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

This missense variant replaces arginine with glutamine at codon 145 in the actin binding region 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). An experimental functional study has shown that this variant reduces the intrinsic inhibitory activity of the cardiac troponin I protein without changing the apparent affinity for actin and increases the Ca2+ sensitivity of cardiac muscle contraction (PMID: 11735257). This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 15607392, 23283745, 24111713, 25132132, 27532257, 28193612, 29255176, 32492895, 32686758, 34137518). In one family, it has been shown that this variant segregates with disease in three individuals affected with hypertrophic cardiomyopathy (PMID: 29255176). This variant has also been reported in individuals suspected to be affected with hypertrophic cardiomyopathy (PMID: 31737537, 33673806) and in an individual affected with restrictive cardiomyopathy (PMID: 21533915). This variant has been identified in 4/248984 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg145Trp and p.Arg145Gly, are considered to be disease-causing (ClinVar variation ID: 12426 and 12419), suggesting that arginine at this position is important for TNNI3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

The variant was co-segregated with Cardiomyopathy, hypertrophic, 7 in multiple affected family members with additional meioses (PMID: 9241277, 15607392, 23283745, 24111713, 25132132, PP1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11735257, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.8, 3CNET: 0.979, PP3_P). A missense variant is a common mechanism associated with Cardiomyopathy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000016, PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012419,VCV000012426, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

The p.Arg145Gln variant in TNNI3 has been reported in 10 individuals with HCM and 1 individual with RCM who also carried a second variant in TNNI3 (Berge 2014, Mogensen 2004, Kimura 1997, van den Wijngaard 2011, Wang 2014, Zou 2013, LMM data). This variant has also been reported in ClinVar (Variation ID 43384) as Pathogenic and Likely pathogenic, and in 2/17246 East Asian and 2/33578 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516349). This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In vitro functional studies provide some evidence that the p.Arg145Gln variant may impact protein function (Takahashi-Yanaga 2001). However, these types of assays may not accurately represent biological function. In addition, 2 other pathogenic variants have been reported at this amino acid position (p.Arg145Gly and p.Arg145Trp), suggesting that this residue has functional importance. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg145Gln variant is likely pathogenic.