ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.433C>G (p.Arg145Gly) (rs104894724)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000557688 SCV000059945 pathogenic Hypertrophic cardiomyopathy 2019-01-31 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000251781 SCV000320677 pathogenic Cardiovascular phenotype 2015-12-21 criteria provided, single submitter clinical testing Thep.R145Gpathogenic mutation(also known as c.433C>G), located in codingexon7 of theTNNI3gene, results from a C to G substitution at nucleotide position 433. Thearginineatcodon145 is replaced byglycine, an amino acid with dissimilar properties.This mutation was reported to co-segregatewith 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.NatGenet.1997;16(4):379-82;Choiet al.ClinCardiol.2010l;33(7):430-8; Zhao Y et al.BiomedRes 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 inassociation with HCM and restrictive cardiomyopathy(Mogensenet al.JClinInvest.2003;111(2):209-16; Mogensen et al. JAm Coll Cardiol. 2004;44(12):2315-25). Furthermore, in vitrostudies and transgenic mouse models suggestthat this mutation resultsin slowed rate and reduced ability of cardiac fibers to relax in the absence of calcium(James et al.CircRes.2000; 87(9):805-11;Langet al.JBiolChem. 2002;277(14):11670-8;Wen et al. J BiolChem. 2008;283(29):20484-94). Based on the supporting evidence, p.R145G is interpreted as a disease-causing mutation.
GeneDx RCV000441050 SCV000517404 pathogenic not provided 2015-06-02 criteria provided, single submitter clinical testing The R145G variant in the TNNI3 gene has been reported to co-segregate with HCM in at least twofamilies (Kimura A et al., 1997; Choi J et al., 2010). In addition, the R145G variant was not observed inapproximately 6,100 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. R145G results in anon-conservative amino acid substitution at a position where amino acids with similar properties to Arginineare tolerated across species. Furthermore, functional studies show that the R145G variant results inincreased thin filament Ca2+ affinity and enhanced Ca2+ binding of troponin complex (Elliot K et al., 2000;Deng Y et al., 2001; Robinson P et al., 2007). Moreover, variants in this residue (R145Q, R145W) and innearby residues (L144P, L144Q, V147L, S150C) have been reported in the Human Gene MutationDatabase in association with HCM (Stenson P et al., 2014), further supporting the functional importance ofthis residue and this region of the protein. In summary, R145G in the TNNI3 gene is interpreted as a pathogenic variant.
Invitae RCV000557688 SCV000623781 pathogenic Hypertrophic cardiomyopathy 2017-05-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 145 of the TNNI3 protein (p.Arg145Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in the population databases (rs104894724, ExAC). This variant has been reported in several individuals with hypertrophic cardiomyopathy (HCM) and has been shown to segregate with disease in an affected family (PMID: 9241277, 20641121). ClinVar contains an entry for this variant (Variation ID: 12419). Experimental studies using several cellular, animal and human models have shown that this variant causes deleterious effects on several aspects of TNNI3 protein function including crossbridge and force kinetics and calcium sensitivity (PMID: 15718266, 11724573, 26391394, 22500102, 19289050, 11735257, 10806205). A different missense substitution at this codon (p.Arg145Trp) has been determined to be pathogenic (PMID: 21533915, 23283745, 27532257, 16531415, 18423659, 19289050, 19651143, 27557662 ). This suggests that the arginine residue is critical for TNNI3 protein function and that other missense substitutions at this position may also be pathogenic For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013231 SCV000033478 pathogenic Familial hypertrophic cardiomyopathy 7 2008-07-18 no assertion criteria provided literature only

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