ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.485G>A (p.Arg162Gln) (rs397516354)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000197981 SCV000059952 likely pathogenic Hypertrophic cardiomyopathy 2020-08-27 criteria provided, single submitter clinical testing The p.Arg162Gln variant in TNNI3 has been reported in >15 individuals with HCM, one of whom was homozygous and 2 of whom also carried other pathogenic variants in MYH7. This variant also segregated with disease in >10 affected relatives from multiple families (Van Driest 2003 PMID:12860912, Mogensen 2004 PMID:15607392, Doolan 2005 PMID:15698845, Cheng 2005 PMID:15992656, Ingles 2005 PMID:16199542, Bos 2006 PMID:16352453, Gruner 2011 PMID:21511876, Rani 2012 PMID:22876777, Kapplinger 2014 PMID:24510615, Mouton 2015 PMID:25940119, Cecconi 2016 PMID 27600940, Burns 2017 PMID 28790153, LMM data). However, the p.Arg162Gln variant was also present in several unaffected relatives, many of whom were older than 50, suggesting reduced penetrance or a milder role (Mogensen 2004 PMID: 15607392, LMM data). This variant did not segregate with disease in 1 affected relative, although this discrepancy may be explained by the presence of more than 1 pathogenic variant in this family or an environmental origin of disease. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43389) and was also identified in 0.005% (6/111598) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies using a mammalian two-hybrid system suggests that this variant may impact protein function by affecting the interaction with other binding partners (troponin T and troponin C; Doolan 2005 PMID:15698845)Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Additionally, two different variants at this position (p.Arg162Pro and p.Arg162Trp) were identified in multiple individuals with HCM (Kimura 1997 PMID:9241277, Richard 2005 PMID:12707239, Doolan 2005 PMID:15698845, Ingles 2005 PMID:16199542, Gray 2013 PMID:23270746, LMM data), suggesting that a change of this amino acid residue is not tolerated. In summary, the p.Arg162Gln variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM; however, this variant may have a milder role suggested by the incomplete penetrance seen in some family members and the individuals who were homozygous or double heterozygous. ACMG/AMP Criteria applied: PS4_Moderate; PP1_Strong; PS3_Supporting; BP4.
GeneDx RCV000159229 SCV000209175 pathogenic not provided 2018-07-30 criteria provided, single submitter clinical testing The R162Q pathogenic variant in the TNNI3 gene has been reported in multiple unrelated patients with HCM (Van Driest et al., 2003; Mogensen et al., 2004; Doolan et al., 2005; Ingles et al., 2005; Rani et al., 2012; Coppini et al., 2014; Kapplinger et al., 2014; Mouton et al., 2015; Restrepo-Cordoba et al., 2017) and affects the arginine 162 residue located within a functionally significant troponin C binding site domain. This variant has been reported to segregate with hypertrophic cardiomyopathy in at least two families (Mogensen et al., 2004; Rani et al., 2012). In addition, in vitro functional studies using HEK293 cells showed that the R162Q variant results in a 50% reduction of the troponin I and troponin C interaction (Doolan et al., 2005). Pathogenic variants in the same residue (R162P, R162W) have also been reported in association with HCM (Stenson et al., 2014), supporting the functional importance of this residue. Moreover, the R162Q is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In summary, R162Q in the TNNI3 gene is interpreted as a pathogenic variant.
Invitae RCV000197981 SCV000253837 pathogenic Hypertrophic cardiomyopathy 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 162 of the TNNI3 protein (p.Arg162Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs397516354, ExAC 0.006%). This variant was shown to segregate with hypertrophic cardiomyopathy in two families (PMID: 15607392, 22876777). In addition, it has been reported in multiple unrelated individuals diagnosed with hypertrophic cardiomyopathy (PMID: 12860912, 15607392, 15698845, 15992656, 16352453). ClinVar contains an entry for this variant (Variation ID: 43389). An experimental study has shown that this missense change decreases the interaction between troponin T and troponin C in a mammalian two-hybrid system (PMID: 15698845). In summary, this is a rare missense change that has been seen in multiple individuals with cardiomyopathy, has been shown to segregate with the phenotype, and has a functional effect in vitro. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000208428 SCV000264251 pathogenic Primary familial hypertrophic cardiomyopathy 2015-07-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000477941 SCV000611326 pathogenic Dilated cardiomyopathy 2A; Familial restrictive cardiomyopathy 1; Dilated cardiomyopathy 1FF; Familial hypertrophic cardiomyopathy 7 2017-05-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620118 SCV000737362 likely pathogenic Cardiovascular phenotype 2020-03-02 criteria provided, single submitter clinical testing The p.R162Q variant (also known as c.485G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 485. The arginine at codon 162 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (e.g., Van Driest SL et al. Circulation. 2003;108(4):445-51; Ingles J et al. J Med Genet. 2005;42(10):e59; Gruner C et al. Circ Cardiovasc Genet. 2011;4(3):288-95; Coppini R et al. J Am Coll Cardiol. 2014;64(24):2589-600; Lopes LR et al. Heart. 2015; 101(4):294-301; Mouton JM et al. Cardiovasc J Afr. 2015; 26(2):63-9; Walsh R et al. Genet. Med. 2017;19:192-203). This variant co-segregated with disease in three families; however, multiple unaffected family members also carried the variant (Mogensen J et al. J Am Coll Cardiol. 2004; 44(12):2315-25; Doolan A et al. J Mol Cell Cardiol. 2005; 38(2):387-93; Rani DS et al. BMC Med Genet. 2012;13:69). In one study, in silico analysis indicated that this alteration may result in reduced protein stability (Ramachandran G et al. PLoS ONE 2013 ; 8(8):e70704). Two likely pathogenic alterations, p.R162P (c.485G>C) and p.R162W (c.484C>T), have been described in the same codon (Kimura A et al. Nat. Genet. 1997;16:379-82; Richard P et al. Circulation. 2003;107:2227-32). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Heart Center,Academic Medical Center Amsterdam RCV000850015 SCV000992157 likely pathogenic Dilated cardiomyopathy 1FF 2018-12-01 criteria provided, single submitter research
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000197981 SCV000996359 pathogenic Hypertrophic cardiomyopathy 2017-03-28 criteria provided, single submitter research TNNI3 Arg162Gln has been identified in multiple HCM probands (Walsh R, et al., 2017; Cecconi M, et al., 2016; Mouton JM, et al., 2015; Coppini R, et la., 2014; Kapplinger JD, et al., 2014; Rani DS, et al., 2012; Bos JM, et al., 2006; Mogensen J, et al., 2004; Van Driest SL, et al., 2003) and has been found to segregate with disease in 2 HCM families (Rani DS, et al., 2012; Mogensen J, et al., 2004). The variant is present at a low frequency in the Exome Aggregation Consortium dataset (MAF=0.00003; http://exac.broadinstitute.org/). We have identified this variant in 3 HCM probands (Burns et al., 2017), one of their families have been previously described (Ingles J, et al., 2005; Doolan A, et al., 2005). Computational tools CADD, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect, however SIFT predicts this variant to be "tolerated". A mammalian two-hybrid system has shown that this missense change decreases troponin T and troponin C interaction (Doolan A, et al., 2005), whereas crystal structure modelling suggests that the Arg162Gln affects troponin C stability (Ramachandran G, et al., 2013). In summary, the TNNI3 Arg162Gln is a rare variant which has been described in multiple HCM probands around the world and has been found to segregate strongly in at least 2 families, therefore we classify this variant as "pathogenic".
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170614 SCV001333203 pathogenic Cardiomyopathy 2018-11-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV001170614 SCV001358527 likely pathogenic Cardiomyopathy 2020-11-02 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 162 of the TNNI3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant disrupts interactions with troponin C and T (PMID: 15698845). However, clinical relevance of this observation is not known. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 12860912, 15607392, 15698845, 15992656, 16352453, 25940119, 31877599, Yang et al 2018). This variant has been shown to segregate with hypertrophic cardiomyopathy in a family study (PMID: 22876777). This variant has also been reported in the homozygous state in an individual affected with severe, early-onset hypertrophic cardiomyopathy (PMID: 31877599). The proband's four relatives were asymptomatic heterozygous carriers. This variant has been identified in 10/249030 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg162Pro and p.Arg162Trp, are known to cause disease (Clinvar variation ID: 43390, 161396), indicating that arginine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000159229 SCV001715301 pathogenic not provided 2019-10-28 criteria provided, single submitter clinical testing PS3, PM5, PM1, PS4_moderate, PP3, PP1
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000159229 SCV000280508 likely pathogenic not provided 2015-07-24 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. The variant has been seen in at least 11 unrelated cases of HCM (not including this patient's family). There is supporting segregation data available. We have seen this variant in one other person with HCM in our clinic. Per the LMM ClinVar summary "the Arg162Gln variant in TNNI3 has been reported in >10 individuals with HCM and segregated with disease in 11 affected family members across several families (Van Driest 2003, Doolan 2005, Mogensen 2004, Ingles 2005, Rani 2012, LMM unpublished data)." In ClinVar GeneDx notes that they have observed the variant in several unrelated individuals tested for HCM (phenotyeps not given). LMM notes "in 1 family tested at our laboratory, the variant was absent in an affected individual, raising additional concerns, although this discrepancy can have multiple explanations including the presence of more than 1 pathogenic variant or an environmental origin of disease." Other variants have been reported in association with disease at this codon (p.Arg162Pro and p. Arg162Gly) . The variant is located within a functionally significant troponin C binding site domain. In silico analysis of R162Q mutant protein demonstrated a decrease in protein stability (Ramachandran et al., 2013). There is also expertimental evidence tha tsuggests this variant dirupts protein-protein interactions. Per the LMM ClinVar submission "arginine (Arg) at position 162 is not conserved in evolutionarily distant species (two bat species, birds, and fish), supporting that a change at this position may be tolerated; however, not all pathogenic variants are conserved in lower species." The variant was reported online in 3 of 60,827 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 24, 2015). Specifically, the variant was observed in 2/33619 Europeans and 1/8314 South Asian. Another variant at the same codon, p.Arg162Trp, is present in 4 of 60,876 individuals in ExAC. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in a dataset like this so this does not necessarily rule out pathogenicity (Pan et al 2012).
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477941 SCV000536702 likely pathogenic Dilated cardiomyopathy 2A; Familial restrictive cardiomyopathy 1; Dilated cardiomyopathy 1FF; Familial hypertrophic cardiomyopathy 7 2014-10-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000159229 SCV001743099 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000159229 SCV001921274 likely pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000159229 SCV001955841 likely pathogenic not provided no assertion criteria provided clinical testing

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