TNNI3

Gene Facts

• HGNC Symbol: TNNI3 (HGNC:11947)
• HGNC Name: troponin I3, cardiac type
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: CMD2A
• Alias symbols: TNNC1, CMH7, cTNI
• %HI: 40.95
• pLI: 0
• LOEUF: 1.1
• Cytoband: 19q13.42
• Genomic Coordinates:

  GRCh37/hg19:	chr19:55663135-55669100
  GRCh38/hg38:	chr19:55151767-55157732

• MANE Select Transcript: NM_000363.5 ENST00000344887.10
• Function: Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-7134
• ClinGen Curation ID: CCID:008022
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 05/25/2023

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• cardiomyopathy, familial restrictive, 1

HI Evidence

• PUBMED: 18006163
  Kostareva et al. (2007) describe a patient with restrictive cardiomyopathy that ultimately resulted the patient’s death at age 28, due to congestive heart failure. This patient carried a single nucleotide deletion in exon 7 of TNNI3 (the penultimate exon), which is predicted to result in a premature stop codon (D168 fs X176). Western blot analysis showed a 50% decrease in TNNI3 levels and no sign of the predicted truncated protein; the authors hypothesize that haploinsufficiency may be the mechanism of action for this variant.
• PUBMED: 28436080
  Bollen et al. (2017), PMID: 28436080 performed functional studies of single isolated membrane-permeabilized cardiomyocytes of a patient with the c.292C>T (p.Arg98*) variant in the TNNI3 gene. The authors found the variant resulted in haploinsufficiency and was associated with increased Ca2+-sensitivity and reduced length-dependent activation. Functional studies showed that the TnI protein levels (the protein encoded by TNNI3) were decreased by over 50% in the patient with the p.Arg98* variant; TnI levels were also decreased in an unrelated individual with a pathogenic TNNT2 variant. Western blot analysis with an appropriate antibody for the N-terminal region of the TNNI3 protein failed to detect the presence of a truncated protein. Both the TNNI3 p.Arg98* variant and the pathogenic TNNT2 variant were associated with decreased levels of the other complex members TnT and TnC (to various extents). Expression of recombinant wildtype troponin complex in TNNI3 p.Arg98* cardiomyocytes was able to increase TnI protein levels and restored Ca2+-sensitivity and length-dependent activation to normal levels. NOTE: This variant is observed at a low frequency in the Genome Aggregation Database (gnomAD) v2.1. AF = 0.0057% (16 HTZ)
• PUBMED: 27532257
  Walsh et al. (2017), PMID: 27532257 - in a cohort of 7,855 clinical cardiomyopathy cases, the c.338del (p.Asp113Alafs*2) variant was identified in an individual with hypertrophic cardiomyopathy, the c.292C>T (p.Arg98*) variant was identified in an individual with hypertrophic cardiomyopathy. Frameshift variants that were not predicted to result in nonsense-mediated decay, c.506del (p.Leu169Argfs*8) and c.538del (p.Asp180Thrfs*19) and c.573G>A (p.Trp191*), were also identified in three individuals with HCM.
• PUBMED: 26688388
  In a cohort of 53 genotype-positive individuals with cardiomyopathy / arrythmia, the c.204del (p.Arg69Alafs*8) variant was identified in an individual screened for cardiomyopathy genes by Chanavat et al. (2016).
• PUBMED: 18533079
  Olivotto et al. (2008) idnetified the .258delC (p.Leu88Trpfs*27) in the heterozygous state in one of 203 patients with HCM; the individual was heterozygous for the TNNI3 variant and a second variant, p.Arg869His, in the MYH7.
• PUBMED: 29095814
  Hu et al. (2018) identified the c.335dupA (p.p.Tyr112*) variant in a male individual with HCM from a cohort of 1,323 patients tested by singleton exome sequencing.

• HI Evidence Comments: NEW TNNI3 encodes a cardiac muscle isoform of Troponin I. Sequence-level variants in TNNI3 are associated with hypertrophic cardiomyopathy (OMIM: 613690), restrictive cardiomyopathy (OMIM: 115210), and dilated cardiomyopathy (OMIMs: 611880-recessive and 613286-dominant). The majority of reported mutations are missense mutations that affect the TNNI3 coding sequence; however, these mutations are not reported to result in a loss of function. Instead, functional studies on these mutations have shown that they affect Ca2+ binding to myofilaments containing the mutant TNNI3 (PMIDs: 16531415 and 22675533) or result in an increased myofilament response to Ca2+ (PMID: 11735257). At this time, there is emerging evidence to support haploinsufficiency of this gene, including functional studies that support decreased protein levels in individuals with truncating variants (PMIDs: 18006163, 28436080). As well, truncating variants have been identified in the heterozygous state in multiple individuals with cardiomyopathy, and were mostly identified from large cohort studies (see examples below). Biallelic truncating variants in the TNNI3 gene have been identified in individuals with severe dilated cardiomyopathy (see PMIDs: 35838873, 36699461, 34036930), and carrier parents without evidence of cardiomyopathy have been reported. As well, individuals with truncating variants in TNNI3 and a complex genotype involving multiple variants in cardiomyopathy genes (see PMIDs: 21835320, 25132132) or truncating variants that are thought to act through a mechanism other than haploinsufficiency (see PMIDs: 21835320, 25132132, 21533915, 34365612) have been identified. Familial segregation data for truncating variants expected to result in haploinsufficiency of the TNNI3 gene is limited. At least one truncating variant has been identified in an apparently healthy individual through a screening study for medically actionable secondary findings (see PMID: 30291343). At this time, loss-of-function/haploinsufficiency is not clearly established as a mechanism of TNNI3-related disorders, and therefore a haploinsufficiency score of 1 is used. Additional putative loss-of-function variants have been identified in the literature, but zygosity was not reported (see PMIDs: 34286374, 25163546). Additional examples of heterozygous loss-of-function variants also exist in the literature, including the c.406C>T (p.Arg136*) variant that was identified in a subject with ARVC from a cohort of 207 patients with suspected inherited cardiomyopathies (Smith et al. (2022), PMID: 35470680).

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: At this time there is no evidence that supports the triplosensitivity of this gene.