ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.433C>T (p.Arg145Trp) (rs104894724)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000498333 SCV000059946 pathogenic Hypertrophic cardiomyopathy 2019-06-28 criteria provided, single submitter clinical testing The p.Arg145Trp variant in TNNI3 has been reported in >25 individuals with HCM or RCM and segregated with disease in >15 affected family members (Yumoto 2005, Mogensen 2004, Andersen 2009, Cheng 2005, Fokstuen 2008, Mogensen 2003, van den Wijngaard 2011, Walsh 2017, Hwang 2017, van Velzen 2018, LMM data). It was shown to be a Dutch founder mutation (van den Wijngaard 2011).This variant has also been identified in 3/280226 chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and reported in ClinVar (Variation ID #12426). Functional studies in muscle fibers from transgenic mice showed an increase in force generation (Wen 2009). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PS3_Moderate.
GeneDx RCV000159222 SCV000209168 pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing The R145W pathogenic variant in the TNNI3 gene has been reported multiple times in association with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) in individuals with variable clinical expression from multiple ethnic backgrounds (Mogensen et al. 2003; Mogensen et al., 2004; Moon et al., 2005; Fokstuen et al., 2008; Andersen et al., 2009; van den Wigngaard et al. 2011; Zou et al., 2013; Hwang et al., 2017). This variant is reported as a founder mutation in the Dutch population (van den Wijngaard et al., 2011). In addition, R145W has been seen in multiple unrelated individuals referred for HCM testing at GeneDx.The R145W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this variant resides in a region of the TNNI3 gene required for inhibition of human cardiac troponin I actomyosin ATPase activity, and functional studies have demonstrated that R145W results in functional impairment including increased Ca2+ sensitivity of both force development and ATPase activity (Gomes et al. 2005; Yumoto et al., 2005; Kobayashi et al., 2006; Wen et al. 2009; Parvatiyar et al., 2010). Other variants affecting the same residue (R145Q, R145G) and nearby residues (R141Q, L144P, L144Q, V147L, S150C) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Finally, the R145W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Center for Human Genetics,University of Leuven RCV000498333 SCV000579511 pathogenic Hypertrophic cardiomyopathy 2017-02-09 criteria provided, single submitter clinical testing ACMG score pathogenic
Invitae RCV000498333 SCV000623782 pathogenic Hypertrophic cardiomyopathy 2020-09-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 145 of the TNNI3 protein (p.Arg145Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs104894724, ExAC 0.006%). This variant has been reported in more than ten individuals and families affected with hypertrophic cardiomyopathy (PMID: 21533915, 23283745, 27532257), as well as several individuals with restrictive cardiomyopathy (PMID: 12531876, 21533915). ClinVar contains an entry for this variant (Variation ID: 12426). Experimental studies have shown that this missense change leads to altered calcium sensitivity and affects ATPase activity (PMID: 16531415, 18423659, 19289050, 19651143, 27557662). A different missense substitution at this codon (p.Arg145Gln) has been determined to be pathogenic (PMID: 9241277, 11735257, 15607392, 23283745, 24111713, 25132132). 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.
Blueprint Genetics RCV000159222 SCV000927140 pathogenic not provided 2017-01-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170617 SCV001333206 pathogenic Cardiomyopathy 2018-03-29 criteria provided, single submitter clinical testing
OMIM RCV000013239 SCV000033486 pathogenic Familial restrictive cardiomyopathy 1 2003-01-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000159222 SCV000280507 likely pathogenic not provided 2014-04-08 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg145Trp (c.433 C>T) in the TNNI3 gene Cardiomyocyte contraction is dependent on local sarcomeric calcium levels, which is regulated by the small troponin complex (three subunits I, C and T). Troponin I binds to the thin filament of the sarcomere and prevent muscle contraction by inhibiting the actomyosin activity of the myosin heavy chain. This inhibitory effect is released by calcium binding to troponin C. Troponin I3 is exclusively expressed in cardiac muscle and plays a centaral role in modulating cardiac muscle contraction and relaxation in response to changes in intracellular calcium. The prevalence of mutation in TNNI3 is believed to be <5% in different types of cardiomyopathies, with most commonly in HCM. This variant is in exon 7. The majority of variants in TNNI3 have been reported in exons 7 and 8. The variant has been seen in at least 10 unrelated cases of HCM or RCM with no segregation data. The p.Arg145Trp variant has been reported previously in association with HCM and restrictive cardiomyopathy (RCM) and the testing lab reports it has also been reported in multiple unrelated individuals testing for HCM at their lab. Mogensen et al (2003) reported this variant in two individuals with restrictive cardiomyopathy. Haplotype did not suggest a common founder effect. These two patients had typical features of RCM diagnosed in their late fifties with symptoms of heart failure. No segregation data was available. Van den Wijngaard et al (2011) reported this variant in eight patients from a cohort of 1040 with cardiomyopathy. 6 of these patients has HCM, one had RCM and one did not have enough information to determine phenotype. No segregation data was indicated. Families carrying the p.Arg145Trp variant showed LVH and ECG typical for HCM. All available ECGs for this cohort showed abnormalities in the patients with this variant. Most patients with this variant showed LVH and clear clinical symptoms between the age of 40-50. In three families, cases of sudden death had occurred: in one family at age 41 (RCM) and in the second family at age 50 (HCM). In the third family two cases of SCD were reported, one at age 13 and one at 38, although the authors could not confirm the presence of this variant in the deceased. In this same family, the sister of the proband who carried the variant was unaffected at age 67. Another proband survived an out-of-hospital cardiac arrest. The authors sate that p.Arg145Trp is the most frequent TNNI3 mutation in the Netherlands (27% of TNNI3 variants). Van den Wijngaard and colleagues performed haplotype analysis and suggest this is a founder mutations in the Dutch population. It has been shown that the sequence required for inhibition of human cardiac troponin I actomyopsin ATPase activity consists of 21 amino acid residues from number 137 to 148 (Syskka H e al., 1976)/ In additional in vitro expression studies have investigated previous reported TNNI3 mutation associated with HCM. Similar findings were reported following analysis of transgenic mice expressing a Arg145Gly variant (James J., 200) Multiple functional studies have noted Arg145Trp is located in the region of the gene that is required for inhibition of human cardiac troponin I actomyosin ATPase activite and Arg145Trp showed a large increase in CA2+ sensitively of both force development, ATPase activity and other functional impairments (Gomes A et al, 2005; Wen Y et al., 2009). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 145 is mostly conserved across species, it is a lysine at that position in C-elegans and D-melanogaster, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (Arg145Gln; Arg145Gly) and nearby codons (Arg141Gln; Arg144Gln; Arg144Pro). In total the variant has not been seen in ~6,610 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 145 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 10/30/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 10/30/13). The variant was not observed in the following laboratory and published control samples: Mogensen reported absence of this variant in 200 chromosomes from Caucasian control individuals. Van den Wijngaard reported these variants were not present in 10 control individuals.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV001254730 SCV001430810 pathogenic Restrictive cardiomyopathy; Hypertrophic cardiomyopathy 2019-01-21 no assertion criteria provided research The TNNI3 Arg145Trp variant has been identified in multiple HCM and RCM patients (Mogensen et al., 2003; Mogensen et al., 2004; Cheng, 2005; Fokstuen et al., 2008; Andersen et al., 2009; van den Wjingaard et al., 2011). The variant has also been shown to segregate with disease in several families (Mogensen et al., 2004; Andersen et al., 2009; van den Wjingaard et al., 2011; Maron et al., 2012). Van den Wjingaard et al., identified this variant in multiple probands, and using haplotype analysis proved that TNNI3 Arg145Trp is a founder mutation in the Dutch population. Furthermore, functional studies have shown that Arg145Trp mutant muscle fibres cause a significant increase in Ca2+ sensitivity for force development as well as ATPase activity, and lack the ability to inhibit human cardiac troponin I actomyosin ATPase activity (Gomes AV, et al., 2005; Yumoto F, et al., 2005; Wu HF, et al., 2007; Wen Y, et al, 2007). The TNNI3 Arg145Trp variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/), at an allele frequency of 0.000012. We identified this variant in a HCM proband with no family history of disease or SCD. Two different rare variants at this position (Arg145Gly and Arg145Gln) have also been reported in multiple HCM individuals suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, MutationTaster, Polyphen-HCM and PolyPhen-2 predict this variant to have a deleterious effect. Based on the adapted ACMG criteria (Kelly MA, et al., 2018), functional studies have shown that this variant causes a damaging effect on the protein (PS3), the variant has reported in more than 10 unrelated HCM probands (PS4), the variant segregates strongly with disease (PP1_Strong), the variant is rare in the general population (PM2) and multiple in silico tools predict this variant to have a deleterious effect (PP3), therefore we classify TNNI3 Arg145Trp as "pathogenic".
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000159222 SCV001744846 pathogenic not provided no assertion criteria provided clinical testing

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