ClinVar Miner

Submissions for variant NM_000363.4(TNNI3):c.434G>A (p.Arg145Gln) (rs397516349)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621089 SCV000740143 likely pathogenic Cardiovascular phenotype 2017-04-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s)
Blueprint Genetics, RCV000208273 SCV000264250 pathogenic Primary familial hypertrophic cardiomyopathy 2015-12-01 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000200141 SCV000579525 likely pathogenic Hypertrophic cardiomyopathy 2017-02-09 criteria provided, single submitter clinical testing ACMG score likely pathogenic
Fulgent Genetics RCV000763057 SCV000893542 pathogenic Dilated cardiomyopathy 2A; Familial restrictive cardiomyopathy 1; Dilated cardiomyopathy 1FF; Familial hypertrophic cardiomyopathy 7 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000159223 SCV000209169 pathogenic not provided 2018-05-18 criteria provided, single submitter clinical testing The R145Q pathogenic variant in the TNNI3 gene has been reported in multiple individuals with HCM (Kimura et al., 1997; Takahashi-Yanaga et al., 2001; Mogensen et al., 2004; Zou et al., 2013; Berge et al., 2014; Wang et al., 2014; Walsh et al., 2017; Weissler-Snir et al., 2017). R145Q was also identified in a mosaic individual with RCM who also harbored a second missense variant in the TNNI3 gene (van den Wijngaard et al., 2011). This variant has also been identified in other unrelated individuals referred for HCM genetic testing at GeneDx, and was found to segregate with disease in three affected relatives from one family. In addition, R145Q is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R145Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies demonstrated that the R145Q variant results in a large increase in the Ca2+ sensitivity of cardiac muscle contraction (Takahashi-Yanaga et al., 2001). Furthermore, other pathogenic missense variants at the same residue (R145G, R145W) have been reported in association with cardiomyopathy (Choi et al., 2010; van den Wijngaard et al., 2011), further supporting the functional importance of this residue.
Invitae RCV000200141 SCV000253695 pathogenic Hypertrophic cardiomyopathy 2017-11-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 145 of the TNNI3 protein (p.Arg145Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs397516349, ExAC 0.01%). This variant has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9241277, 15607392, 23283745, 24111713, 25132132). ClinVar contains an entry for this variant (Variation ID: 43384). Experimental studies have shown that this missense change increases the calcium sensitivity of cardiac muscle contraction in vitro (PMID: 11735257). Two different amino acid changes at this position (Arg145Trp and Arg145Gly) have been reported as pathogenic sequence changes (PMID: 11735257, 20641121, 23610579), indicating that this amino acid position is important for TNNI3 protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000208273 SCV000059947 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-09-08 criteria provided, single submitter clinical testing 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) 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000159223 SCV000748022 pathogenic not provided 2017-04-19 criteria provided, single submitter clinical testing

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