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ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000019.9) (NC_000019.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
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, 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, which is suggestive of a haploinsufficiency mechanism for this mutation.

Haploinsufficiency phenotype comments:

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 limited evidence to support haploinsufficiency of this gene. The only evidence supporting the haploinsufficiency of TNNI3 is a single report of a patient with a single nucleotide deletion in TNNI3 that resulted in decreased TNNI3 protein levels (PMID: 18006163). There are currently no reported TNNI3 whole gene deletions. Please note that there are additional indel/splice site mutations that have been reported in this gene. These mutations either do not have functional data to support a loss of function disease mechanism (PMID: 20474083, 25524337, 24111713, 12707239, 25940119, and 18467357), are thought to be associated with a mechanism other than loss of function (PMID: 11735257 and 21533915), or have a complex genotype (PMID: 21835320 and 25132132).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

At this time there is no evidence that supports the triplosensitivity of this gene.