TNNI3

troponin I3, cardiac type, the group of Troponin complex subunits

Basic information

Region (hg38): 19:55151767-55157773

Previous symbols: [ "CMD2A" ]

Links

ENSG00000129991 ∙ NCBI:7137 ∙ OMIM:191044 ∙ HGNC:11947 ∙ Uniprot:P19429 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypertrophic cardiomyopathy 7 (Strong), mode of inheritance: AD
• hypertrophic cardiomyopathy 7 (Strong), mode of inheritance: AR
• familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
• familial isolated restrictive cardiomyopathy (Supportive), mode of inheritance: AD
• dilated cardiomyopathy 2A (Definitive), mode of inheritance: AR
• hypertrophic cardiomyopathy 7 (Definitive), mode of inheritance: AD
• cardiomyopathy, familial restrictive, 1 (Strong), mode of inheritance: AD
• dilated cardiomyopathy 1FF (Strong), mode of inheritance: AD
• dilated cardiomyopathy 2A (Strong), mode of inheritance: AR
• hypertrophic cardiomyopathy 7 (Strong), mode of inheritance: AD
• arrhythmogenic right ventricular cardiomyopathy (No Known Disease Relationship), mode of inheritance: AD
• hypertrophic cardiomyopathy (Definitive), mode of inheritance: AD
• dilated cardiomyopathy (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cardiomyopathy, familial hypertrophic 7; Cardiomyopathy, dilated 1FF; Cardiomyopathy, dilated, 2A; Cardiomyopathy, familial restrictive 1	AD/AR	Cardiovascular	Preventive measures, surveillance (eg, including echocardiography and electrocardiography), and medical management may be helpful to decrease morbidity; Cardiac transplantation has been reported	Cardiovascular	3594932; 9241277; 9753711; 12531876; 15070570; 16267253; 19590045; 20569525; 21846512; 22301726; 22455086; 22876777; 23349452; 23396983; 23906401

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TNNI3 gene.

• not provided (7 variants)
• Hypertrophic cardiomyopathy (7 variants)
• Cardiomyopathy, familial restrictive, 1 (4 variants)
• Cardiovascular phenotype (4 variants)
• Hypertrophic cardiomyopathy 7 (3 variants)
• Cardiomyopathy (2 variants)
• SUDDEN INFANT DEATH SYNDROME (2 variants)
• Hypertrophic cardiomyopathy;Restrictive cardiomyopathy (1 variants)
• Restrictive cardiomyopathy (1 variants)
• Restrictive cardiomyopathy;Hypertrophic cardiomyopathy (1 variants)
• Primary familial hypertrophic cardiomyopathy (1 variants)
• TNNI3-related disorder (1 variants)
• Dilated cardiomyopathy 2A (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TNNI3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	104		106
missense	11	31	254	3		299
nonsense	2		9			11
start loss			1			1
frameshift			14			14
inframe indel			5			5
splice donor/acceptor (+/-2bp)		2	12			14
splice region			20	25		45
non coding			14	72	19	105
Total	13	33	311	179	19

Highest pathogenic variant AF is 0.0000197

Variants in TNNI3

This is a list of pathogenic ClinVar variants found in the TNNI3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-55151790-T-C		Cardiomyopathy, familial restrictive, 1 • Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome • Dilated cardiomyopathy 2A • Hypertrophic cardiomyopathy 7	Uncertain significance (Apr 27, 2017)
19-55151799-G-A		Dilated cardiomyopathy 2A • Hypertrophic cardiomyopathy 7 • Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome • Cardiomyopathy, familial restrictive, 1	Conflicting classifications of pathogenicity (Jan 12, 2018)
19-55151818-C-T			Benign (Mar 03, 2015)
19-55151831-G-A		Cardiomyopathy • Hypertrophic cardiomyopathy	Likely benign (Jul 10, 2023)
19-55151832-G-A		Hypertrophic cardiomyopathy	Uncertain significance (Jul 29, 2024)
19-55151835-C-A		not specified • Hypertrophic cardiomyopathy	Uncertain significance (Dec 01, 2023)
19-55151835-C-G		Hypertrophic cardiomyopathy	Uncertain significance (Jun 26, 2023)
19-55151838-C-T		Cardiovascular phenotype	Uncertain significance (Oct 11, 2021)
19-55151839-T-C		Hypertrophic cardiomyopathy	Uncertain significance (Apr 26, 2023)
19-55151840-C-G		Cardiomyopathy, familial restrictive, 1	Uncertain significance (-)
19-55151841-T-G		Hypertrophic cardiomyopathy • Cardiovascular phenotype	Uncertain significance (Sep 09, 2024)
19-55151842-C-T		Hypertrophic cardiomyopathy	Uncertain significance (Apr 18, 2022)
19-55151842-C-CA		Familial restrictive cardiomyopathy	Conflicting classifications of pathogenicity (Jul 03, 2019)
19-55151843-A-C		not specified	Uncertain significance (Jan 22, 2016)
19-55151845-A-T		not specified	Uncertain significance (Jul 06, 2015)
19-55151846-C-G		Hypertrophic cardiomyopathy	Uncertain significance (Sep 12, 2019)
19-55151847-T-C		Hypertrophic cardiomyopathy • Cardiomyopathy, familial restrictive, 1;Dilated cardiomyopathy 2A;Dilated cardiomyopathy 1FF;Hypertrophic cardiomyopathy 7 • Cardiomyopathy	Uncertain significance (Sep 23, 2024)
19-55151849-T-C			Likely benign (Jun 15, 2018)
19-55151850-T-A			Pathogenic (Apr 03, 2013)
19-55151851-T-C			Pathogenic (Jun 28, 2013)
19-55151851-T-G		Hypertrophic cardiomyopathy 7	Pathogenic (Aug 01, 1997)
19-55151852-C-A		Hypertrophic cardiomyopathy	Uncertain significance (Nov 13, 2023)
19-55151853-T-G		Cardiovascular phenotype	Uncertain significance (Mar 06, 2023)
19-55151854-T-G		not specified	Uncertain significance (Nov 03, 2014)
19-55151855-G-C		Cardiomyopathy	Likely benign (Jan 06, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TNNI3	protein_coding	protein_coding	ENST00000344887	8	6005

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0963	0.897	124765	0	33	124798	0.000132

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.28	89	130	0.684	0.00000851	1338
Missense in Polyphen		25	43.109	0.57993		448
Synonymous	-0.441	56	52.0	1.08	0.00000308	415
Loss of Function	2.35	4	13.2	0.303	7.23e-7	147

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000329	0.000306
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000556	0.0000556
Finnish	0.0000464	0.0000464
European (Non-Finnish)	0.000161	0.000159
Middle Eastern	0.0000556	0.0000556
South Asian	0.0000987	0.0000980
Other	0.000330	0.000330

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
• Disease: DISEASE: Cardiomyopathy, familial hypertrophic 7 (CMH7) [MIM:613690]: A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. {ECO:0000269|PubMed:11815426, ECO:0000269|PubMed:12707239, ECO:0000269|PubMed:12974739, ECO:0000269|PubMed:16199542, ECO:0000269|PubMed:9241277}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, familial restrictive 1 (RCM1) [MIM:115210]: A heart disorder characterized by impaired filling of the ventricles with reduced diastolic volume, in the presence of normal or near normal wall thickness and systolic function. {ECO:0000269|PubMed:12531876}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 2A (CMD2A) [MIM:611880]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:15070570}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1FF (CMD1FF) [MIM:613286]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:19590045, ECO:0000269|PubMed:21846512}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cardiac muscle contraction - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Cardiac Progenitor Differentiation;Striated Muscle Contraction;Ion homeostasis;Striated Muscle Contraction;Cardiac conduction;Muscle contraction (Consensus)

Recessive Scores

• pRec: 0.382

Intolerance Scores

• rvis_EVS: 0.15
• rvis_percentile_EVS: 64.11

Haploinsufficiency Scores

• pHI: 0.625
• hipred: Y
• hipred_score: 0.659
• ghis: 0.403

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.826

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Tnni3
• Phenotype: cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; muscle phenotype

Gene ontology

• Biological process: vasculogenesis;regulation of systemic arterial blood pressure by ischemic conditions;skeletal muscle contraction;cellular calcium ion homeostasis;muscle contraction;regulation of smooth muscle contraction;heart development;regulation of cardiac muscle contraction by calcium ion signaling;muscle filament sliding;negative regulation of ATPase activity;ventricular cardiac muscle tissue morphogenesis;heart contraction;cardiac muscle contraction
• Cellular component: cytosol;troponin complex;sarcomere;cardiac myofibril;cardiac Troponin complex
• Molecular function: actin binding;protein binding;calcium channel inhibitor activity;protein kinase binding;protein domain specific binding;troponin C binding;troponin T binding;metal ion binding;calcium-dependent protein binding;actin filament binding