TNNI3

Inheritance Pattern: AD

Disease ID:MONDO:0013211

Submitter: ClinGen

The TNNI3 gene was originally evaluated for DCM by the ClinGen DCM GCEP on 05/22/2020 for autosomal dominant DCM. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 3/7/2025. As a result, the classification changed. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. Human genetic evidence supporting this gene-disease relationship includes case-level data. At least 17 variants have been reported in humans with DCM with the vast majority being missense variants. In addition, this gene-disease assertion is supported by expression studies, in vitro functional assays, protein interaction studies and studies showing rescue in patient cells (PMID: 2226790, 19590045, 29093449, 28436080, 36157491). In summary, there is strong evidence to support the relationship between TNNI3 and AD DCM. Although independent reports over a 3 year period contributed to this curation, the panel elected to classify as Strong to allow additional evidence to accumulate for this newly curated MOI for TNNI3 before upgrading to a Definitive classification. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 4/18/2025 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: ClinGen

There is only one case reported of a TNNI3 variant in an ARVC patient (30385303) in a Chinese patient. This proband presented in VT of LBBB superior axis morphology and has TWI in leads V1-V4, meeting ARVC TFC criteria. This variant, however is present in higher than expected prevalence in the East Asian population. Otherwise, in other studies (29709087) of 137 patients sequenced for TNNI3, no pathogenic variants were found. Therefore, there is currently no evidence to suggest a role of TNNI3 in pathogenesis of ARVC.

Inheritance Pattern: AD

Disease ID:MONDO:0019150

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012746

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013369

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013211

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012746

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0013369

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

The TNNI3 gene has been associated with hypertrophic cardiomyopathy. TNNI3 was first associated with this disease in humans in 1997 (Kimura et al, PMID 9241277). At least 60 unique variants, with varying levels of evidence to support their pathogenicity, have been reported in humans (reviewed in Mogensen et al, 2015, PMID 26440512). Variants in this gene segregated with disease in at least 6 families (Kimura et al, 1997, PMID 9241277; Rani et al, 2012, PMID 22876777; Choi et al, 2010, PMID 20641121; Mogensen et al, 2004, PMID 15607392). More evidence is available in the literature , but the maximum score for genetic evidence (12 pts) was reached. The mechanism for disease is likely dominant negative, as 91% of mutations reported are missense variants (Mogensen et al, 2015, PMID 26440512). The gene-disease association is supported by the function of the gene product, animal models, and in vitro assays. In summary, TNNI3 is definitively associated with hypertrophic cardiomyopathy. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Committee, subgroup of the ClinGen Cardiovascular Working Group, on September 5, 2017.

Inheritance Pattern: AD

Disease ID:MONDO:0007270

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012746

Submitter: ClinGen

TNNI3 was first reported in relation to autosomal recessive DCM in 2004 (Murphy et al., 2004, PMID: 15070570). The TNNI3 gene was originally evaluated for DCM by the ClinGen DCM GCEP on 06/12/2020 for autosomal recessive DCM. At that time, a gene-disease relationship was not established between TNNI3 and autosomal recessive DCM. Evidence of the association of this gene with autosomal recessive DCM was re-evaluated using SOP v10 on 3/7/2025. As a result, the classification changed. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. Human genetic evidence supporting this gene-disease relationship includes case-level data. The mechanism of pathogenicity appears to be loss-of-function (LOF). At least 8 variants (including missense, nonsense, frameshift, splice site and large deletion) have been reported in humans with autosomal recessive DCM, typically causing pediatric onset, rapidly progressive disease. The c.204del (p.Arg69Alafs*8) variant appears to be a recurrent variant identified in at least 9 probands. In addition, this gene-disease assertion is supported by in vitro functional assays and protein interaction studies (PMID: 15070570, 22940544). In summary, there is strong evidence to support the relationship between TNNI3 and autosomal recessive DCM. Although independent reports over a 3 year period contributed to this curation, the panel elected to classify as Strong to allow additional evidence to accumulate for this newly curated MOI for TNNI3 before upgrading to a Definitive classification. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 4/18/2025 (SOP Version 10).