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rs104894724

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000363.5(TNNI3):c.433C>T(p.Arg145Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R145G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 missense

Scores

14
5
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 2.31
Variant links:
Genes affected
TNNI3 (HGNC:11947): (troponin I3, cardiac type) Troponin I (TnI), along with troponin T (TnT) and troponin C (TnC), is one of 3 subunits that form the troponin complex of the thin filaments of striated muscle. TnI is the inhibitory subunit; blocking actin-myosin interactions and thereby mediating striated muscle relaxation. The TnI subfamily contains three genes: TnI-skeletal-fast-twitch, TnI-skeletal-slow-twitch, and TnI-cardiac. This gene encodes the TnI-cardiac protein and is exclusively expressed in cardiac muscle tissues. Mutations in this gene cause familial hypertrophic cardiomyopathy type 7 (CMH7) and familial restrictive cardiomyopathy (RCM). Troponin I is useful in making a diagnosis of heart failure, and of ischemic heart disease. An elevated level of troponin is also now used as indicator of acute myocardial injury in patients hospitalized with moderate/severe Coronavirus Disease 2019 (COVID-19). Such elevation has also been associated with higher risk of mortality in cardiovascular disease patients hospitalized due to COVID-19. [provided by RefSeq, Aug 2020]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000363.5
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-55154146-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 12419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 19-55154146-G-A is Pathogenic according to our data. Variant chr19-55154146-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154146-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TNNI3NM_000363.5 linkuse as main transcriptc.433C>T p.Arg145Trp missense_variant 7/8 ENST00000344887.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNNI3ENST00000344887.10 linkuse as main transcriptc.433C>T p.Arg145Trp missense_variant 7/81 NM_000363.5 P1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
151978
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248876
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135084
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461034
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726816
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
151978
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74224
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:8
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 15, 2022Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16020591, 18423659, 19651143, 27557662, 31513939, 23508784, 32492895, 15961398, 15992656, 16288990, 17599605, 18409188, 19035361, 19914256, 20617149, 23283745, 19289050, 28166811, 28382084, 28650931, 27766529, 28181243, 21310275, 25351510, 27532257, 12531876, 28790153, 29661763, 31308319, 33087929, 30847666, 31447099, 32480058, 33673806, 32686758, 24704860, 35027292, 16531415, 15607392, 21533915) -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsJan 31, 2017- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely pathogenic, no assertion criteria providedclinical testingStanford Center for Inherited Cardiovascular Disease, Stanford UniversityApr 08, 2014Note 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 neigh -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Hypertrophic cardiomyopathy Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJul 07, 2023The c.433C>T (p.Arg145Trp) variant in the TNNI3 gene is located on the exon 7 of the TNNI3 gene and is predicted to replace arginine with tryptophan at codon 145 of the TNNI3 protein (p.Arg145Trp). This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) (PMID: 12531876, 15607392, 15992656, 16288990, 18409188, 19035361, 21533915, 23283745, 27532257, 28382084, 29661763) and segregate with diseases (PMID: 15607392, 19035361, 21533915, 21839045). This variant is a founder mutation in the Dutch population (PMID: 21533915). Functional studies showed that this variant leads to increased calcium sensitivity of both force development and ATPase activity (PMID: 15961398, 16288990, 16531415, 18269819, 18423659, 19289050, 19651143, 27557662). Other missense variants affecting the same amino acid residue (Arg145Gly and Arg145Gln) have been reported to be pathogenic. Computational evidence supports a deleterious effect on the protein structure and function. This variant has been observed at a low frequency (3/280226) in the general population according to gnomAD. Therefore, the c.433C>T (p.Arg145Trp) variant in the TNNI3 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 21, 2024This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 145 of the TNNI3 protein (p.Arg145Trp). This variant is present in population databases (rs104894724, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy and restrictive cardiomyopathy (PMID: 12531876, 21533915, 23283745, 27532257). ClinVar contains an entry for this variant (Variation ID: 12426). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 16531415, 18423659, 19289050, 19651143, 27557662). This variant disrupts the p.Arg145 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9241277, 11735257, 15607392, 23283745, 24111713, 25132132). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 28, 2019The 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. -
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, University of LeuvenFeb 09, 2017ACMG score pathogenic -
Cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMay 01, 2020Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene and both mechanisms have been functionally proven with missense variants (PMID: 21533915). (N) 0108 - This gene is known to be associated most commonly with dominant disease, however there is low evidence of association with recessive disease (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 15607392). (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a tryptophan (exon 7). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (4 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif, (troponin domain; PDB, NCBI). (N) 0702 – Comparable missense variants at the same residue (p.Arg145Gly, p.Arg145Gln) have strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (ClinVar, LOVD). (P) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) (ClinVar, LOVD, PMID: 28382084). (P) 0903 - Evidence for segregation with disease in a family with both HCM and RCM (PMID: 28382084). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Transgenic mice were shown to have increased ATPase activity and longer muscle contractions (PMID: 19651143). (P) 1208 – Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioMar 07, 2023- -
Hypertrophic cardiomyopathy;C0007196:Restrictive cardiomyopathy Pathogenic:1
Pathogenic, no assertion criteria providedresearchAgnes Ginges Centre for Molecular Cardiology, Centenary InstituteJan 21, 2019The 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". -
Cardiomyopathy, familial restrictive, 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2003- -
TNNI3-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 27, 2024The TNNI3 c.433C>T variant is predicted to result in the amino acid substitution p.Arg145Trp. This variant was reported in numerous individuals with restrictive cardiomyopathy or hypertrophic cardiomyopathy (Mogensen et al. 2003. PubMed ID: 12531876; van den Wijngaard et al. 2011. PubMed ID: 21533915; Table S1A, Walsh et al. 2017. PubMed ID: 27532257; Table S2, Bagnall et al. 2022. PubMed ID: 36252119). Functional studies supported that this variant impacts normal protein function (described as p.Arg146Trp, Mathur et al. 2009. PubMed ID: 19289050; Wen et al. 2009. PubMed ID: 19651143; Dvornikov et al. 2016. PubMed ID: 27557662). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. Different nucleotide substitutions affecting the same amino acid (p.Arg145Gly and p.Arg145Gln) have been reported in individuals with hypertrophic cardiomyopathy (Human Gene Mutation Database). Taken together, the c.433C>T (p.Arg145Trp) variant is interpreted as pathogenic. -
SUDDEN INFANT DEATH SYNDROME Pathogenic:1
Pathogenic, criteria provided, single submitterresearchRobert's Program, Boston Children's HospitalOct 01, 2021We classify this variant as pathogenic using the following ACMG/AMP criteria: PS3, PS1, PP1, PP5 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
CardioboostCm
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.39
Cadd
Pathogenic
27
Dann
Pathogenic
1.0
DEOGEN2
Pathogenic
0.97
D;D
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.52
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.8
M;.
MutationTaster
Benign
0.99
D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-6.6
D;.
REVEL
Pathogenic
0.82
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.90
MutPred
0.92
Loss of disorder (P = 0.0138);.;
MVP
0.96
MPC
1.7
ClinPred
1.0
D
GERP RS
0.79
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104894724; hg19: chr19-55665514; COSMIC: COSV52572598; COSMIC: COSV52572598; API