ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.575G>A (p.Arg192His) (rs104894729)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154212 SCV000203865 pathogenic Restrictive cardiomyopathy; Hypertrophic cardiomyopathy 2019-05-02 criteria provided, single submitter clinical testing The p.Arg192His variant in TNNI3 has been reported in 9 individuals with predominantly childhood onset RCM or HCM and occurred de novo in 4 of these cases (Mogensen 2003, Gomes 2005, Rai 2009, Yang 2013, LMM data). This variant has not been identified in large population studies. In vitro studies have shown that the p.Arg192His variant impacts protein function (Gomes 2005, Kobayashi 2006, Davis 2007, Mathur 2009, Davis 2010, Liu 2012) and mouse models of this variant develop a restrictive cardiomyopathy phenotype (Du 2006, Du 2008). Finally, other likely disease-causing variants at this position (p.Arg192Cys, p.Arg192Leu) have been identified in individuals with RCM and HCM (Millat 2010, van den Wijngaard 2011, LMM data). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RCM and HCM. ACMG/AMP Criteria applied: PS3, PS4_Moderate, PM6_Strong, PM2, PM5.
GeneDx RCV000159242 SCV000209188 pathogenic not provided 2017-08-21 criteria provided, single submitter clinical testing The R192H variant in the TNNI3 gene has been reported in multiple individuals with early onset restrictive cardiomyopathy (RCM) (Mogensen et al., 2003; Rai et al., 2009; Chen et al., 2014). Mogensen et al. (2003) also did not observe the variant in either parent of an affected proband. Furthermore, functional studies demonstrate that R192H increases Ca2+ sensitivity compared to wild-type and increases the binding affinity of the thin filament (Gomes et al., 2005; Kobayashi et al., 2006; Liu et al., 2012). Additionally, Du et al. (2006) demonstrated that transgenic mice harboring the mouse equivalent of R192H exhibit features characteristic of RCM. Although the R192H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, it occurs at a position that is conserved across species. Finally, the R192H is not observed in large population cohorts (Lek et al., 2016).
Ambry Genetics RCV000619328 SCV000740036 pathogenic Cardiovascular phenotype 2017-12-18 criteria provided, single submitter clinical testing The p.R192H pathogenic mutation (also known as c.575G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 575. The arginine at codon 192 is replaced by histidine, an amino acid with highly similar properties. This mutation has been reported in multiple individuals with restrictive cardiomyopathy and/or hypertrophic cardiomyopathy, often with a de novo or likely de novo origin (Mogensen J et al. J. Clin. Invest. 2003;111:209-16; Rai TS et al. Mol. Cell. Biochem. 2009;331:187-92; Alfares AA et al. Genet. Med. 2015;17:880-8; Chen Y et al. J Biomed Res. 2014;28:59-63; Thomas TO et al. Pediatr Transplant. 2015;19:E15-8; Kohda M et al. PLoS Genet. 2016;12:e1005679). Numerous in vitro functional assays, cardiomyocyte cell culture experiments, and mouse models have all indicated that p.R192H results in deficient function of the TNNI3 protein (e.g., Gomes AV et al. J. Biol. Chem. 2005;280:30909-15; Davis J et al. Circ. Res. 2007;100:1494-502; Du J et al. Am. J. Physiol. Heart Circ. Physiol. 2008;294:H2604-13; Liu B et al. PLoS ONE. 2012;7:e38259). In addition, two other alterations associated with RCM and/or HCM, p.R192C and p.R192L, have been described in the same codon (Millat G et al. Clin. Chim. Acta. 2010;411:1983-91; van den Wijngaard A et al. Neth Heart J. 2011;19:344-51; Alfares AA et al. Genet. Med. 2015;17:880-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000629012 SCV000749922 pathogenic Hypertrophic cardiomyopathy 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 192 of the TNNI3 protein (p.Arg192His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to have arisen de novo in several individuals affected with hypertrophic cardiomyopathy (PMID: 25611685) and in an individual affected with restrictive cardiomyopathy (PMID: 12531876). ClinVar contains an entry for this variant (Variation ID: 12424). Experimental studies have shown that this missense change alters the response of filaments to calcium, slows relaxation, and affects contractile function. In addition, transgenic mice with TNNI3 with this variant exhibit a phenotype similar to human restrictive cardiomyopathy (PMID: 18408133, 17463320, 22675533, 19289050, 20161772, 18423659, 17027633, 16531415). For these reasons, this variant has been classified as Pathogenic.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852483 SCV000995178 pathogenic Restrictive cardiomyopathy 2018-01-03 criteria provided, single submitter clinical testing
OMIM RCV000013237 SCV000033484 pathogenic Familial restrictive cardiomyopathy 1 2003-01-01 no assertion criteria provided literature only
Blueprint Genetics RCV000157534 SCV000207280 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-08-22 no assertion criteria provided clinical testing

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