ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene, where missense have been functionally proven to cause both mechanisms (PMID: 21533915). (I) 0107 - This gene is associated with autosomal dominant disease. Only a single family has been reported with a recessive form of inheritance (PMID 15070570). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 15607392). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD v2 (Highest allele count: 4 heterozygotes, 0 homozygotes). (I) 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, PDB, NCBI). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Arg145Gln) and p.(Arg145Trp) have been reported in cardiomyopathy patients (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Several patients with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) have been reported to harbour this variant (ClinVar; PMID: 20641121). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has been shown to segregate in a large hypertrophic cardiomyopathy Chinese family with a total of 5 genotyped affecteds (PMID: 20641121). SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated loss of inhibitory functions towards actin-myosin interactions (PMID: 11801593). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Not observed at significant frequency in large population cohorts (gnomAD); Transgenic mouse model expressing p.(R145G) showed cardiomyocyte disarray, interstitial fibrosis and premature death, as well as increased CA2+ sensitivity (PMID: 11055985); 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: 10806205, 11735257, 11724573, 15718266, 16531415, 17932326, 24418317, 19289050, 22500102, 20161772, 20641121, 9241277, 26391394, 21310275, 25606687, 27532257, 29760186, 28498465, 11801593, 18430738, 34018815, 33407484, 11055985)

The p.Arg145Gly variant in TNNI3 has been reported in 3 individuals with HCM and segregated with disease in 10 affected relatives from 2 families (Kimura 1997, Choi 2010, LMM data). This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg145Gly variant may impact protein function (Elliott 2000, Deng 2001, Kruger 2005, Robinson 2007). 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). Additionally, two other disease-causing variants have been reported in this codon (p.Arg145Trp, p.Arg145Gln), further suppporting that changes in this codon are not tolerated. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. ACMG/AMP Criteria applied: PP1_Strong; PM2; PM5; PS3_Moderate; PP3; PS4_Supporting.

The p.R145G pathogenic mutation (also known as c.433C>G), located in coding exon 7 of the TNNI3 gene, results from a C to G substitution at nucleotide position 433. The arginine at codon 145 is replaced by glycine, an amino acid with dissimilar properties. This mutation was reported to co-segregate with hypertrophic cardiomyopathy (HCM), apical hypertrophy, and related features in a large Korean family and was also reported in a Chinese proband with HCM (Kimura et al. Nat Genet. 1997;16(4):379-82; Choi et al. Clin Cardiol. 2010l;33(7):430-8; Zhao Y et al. Biomed Res Int. 2015;2015:561819). In addition, other alterations affecting the same amino acid, p.R145Q (c.434G>A) and p.R145W (c.433C>T), have been reported in association with HCM and restrictive cardiomyopathy (Mogensen et al. J Clin Invest. 2003;111(2):209-16; Mogensen et al. J Am Coll Cardiol. 2004;44(12):2315-25). Furthermore, in vitro studies and transgenic mouse models suggest that this mutation results in slowed rate and reduced ability of cardiac fibers to relax in the absence of calcium (James et al. Circ Res. 2000; 87(9):805-11; Lang et al. J Biol Chem. 2002;277(14):11670-8; Wen et al. J Biol Chem. 2008;283(29):20484-94). Based on the supporting evidence, p.R145G is interpreted as a disease-causing mutation.

For these reasons, this variant has been classified as Pathogenic. 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: 16531415, 18423659, 19289050, 19651143, 21533915, 23283745, 27532257, 27557662). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 10806205, 11724573, 11735257, 15718266, 19289050, 22500102, 26391394). 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: 12419). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9241277, 20641121). It has also been observed to segregate with disease in related individuals. 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 145 of the TNNI3 protein (p.Arg145Gly).