Submission Details

TNNC1 was originally evaluated for DCM by ClinGen DCM GCEP on July 10, 2020. Evidence of the association of this gene with DCM was re-evaluated on April 18, 2025. As a result, the classification did not change. A summary of the information contributing to the classification of the gene at the time of re-evaluation is summarized herein.

TNNC1 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2004 (Mogensen et al., 2004, PMID 15542288). The role of TNNC1 as a key component of the troponin complex was demonstrated multiple times since the early 1970s (e.g., Spudich and Watt, 1971, PMID 4254541; Ebashi, 1972, PMID 4634985). The high expression levels of TNNC1 in the cardiac muscle were also highlighted in several studies (e.g., Schreier et al., 1990, PMID 2250022), as is the case for the direct protein-protein interactions with Troponin I (encoded by TNNI3) and Troponin T (encoded by TNNT2) (e.g., Mogensen et al., 2004, PMID 15542288; Baryshnikova et al., 2008, PMID 18803402). Human evidence supporting this gene-disease relationship includes case-level, case-control and segregation data. At least 15 distinct variants were reported in humans with DCM in the literature, and a significant case-control enrichment of rare non-truncating variants in TNNC1 was demonstrated using the Exome Aggregation Consortium cohort as a control cohort (Mazzarotto et al., 2020, PMID 31983221). The p.G159D variant was observed to segregate with DCM in a 5-generation family (Kaski et al., 2007, PMID 17977476), and the effect of p.G159D was characterized functionally using human cardiomyocytes from the explanted heart of the proband of Kaski et al. (Dyer et al., 2009, PMID 19808376) and from other carrier patients (Vikhorev et al., 2017, PMID 29093449). Functional evidence in support of the impact of p.G159D was presented in a large number of studies using different types of in vitro assays between 2004 and 2013 (Mogensen et al., 2004, PMID 15542288; Mirza et al., 2005, PMID 15923195; Preston et al., 2006, PMID 17021793; Biesadecki et al., 2007, PMID 17446435, Robinson et al., 2007, PMID 17932326; Baryshnikova et al., 2008, 18803402; Memo et al., 2013, 23539503) and in one study relying on in silico modeling (Dewan et al., 2016, PMID 27133568). Results of these studies collectively show the variant to abolish the relationship between the phosphorylation status of Troponin I and several properties that regulate myofilament function. Segregation and functional evidence using recombinant human mutant Troponin C were published also for p.Y5H, p.D145E, p.M103I and p.I148V (Pinto et al., 2011, PMID 21832052). These variants had previously been identified in 4/312 DCM patients by the same group (Hershberger et al., 2010, PMID 20215591). The p.Y5H variant, as well as p.I148V and p.M103I were shown to alter several myofilament function properties compatible with DCM. Conversely, p.D145E was characterized by properties more typical of hypertrophic cardiomyopathy (HCM, e.g. increased activation of the ATPase activity), and had been studied earlier in the context of HCM by the same group. In 2019, p.D145E was found in two siblings with DCM in compound heterozygosity with p.D132N, with each variant inherited from a healthy parent (Landim-Vieira, 2019, PMID 32038292). The two variants p.E59D and p.D75Y were found in compound heterozygosity in a DCM patient, and functionally characterized together as well as in isolation (Lim et al., 2008, PMID 18212018). In all the analyzed contractility-related properties (Calcium sensitivity, % cell shortening, molecular motions), the p.D75Y variant had effects comparable to those observed in presence of both variants, while p.E59D was functionally benign and was later proposed as a modifier exacerbating the effect of p.D75Y (Dweck et al., 2009, PMID 20371872). The p.Q50R variant was identified in multiple affected members of the family of a 30-year old proband with peripartum cardiomyopathy (van Spaendonck-Zwarts, 2010, PMID 20458010; van Spaendonck-Zwarts, 2014, PMID 24558114), and p.D3V was found in 1/21 patients in a small Chinese cohort (Zhao et al., 2015, PMID 26458567). The p.I4M variant was found to be de novo in a pediatric DCM patient sequenced with whole-exome sequencing alongside her parents, and was functionally characterized showing significant alterations to several myofilament properties compatible with DCM (Johnston et al., 2019, PMID 31748410). In addition, this gene-disease assertion is supported by several in vitro functional assays and animal models. In a study from 2010, authors generated 20 TNNC1 variants — not clinically observed — that, based on their predicted effects on Calcium sensitivity, were likely to result in different cardiomyopathies. Both p.E40A and p.I61Q resulted in having DCM properties, with myofilaments recapitulating the functional phenotype of clinically observed variants (Parvatiyar et al., 2010, PMID 20566645). Animal models comprise a knock-out Zebrafish recapitulating human DCM with high mortality and reduced heart rate (Ho et al., 2009, PMID 19609041), two mouse models carrying p.D73N (not clinically observed but engineered to reduce myofilament Calcium sensitivity), where heterozygous mice recapitulate human DCM with ECG anomalies, sudden cardiac death and (in 25% mice) atrial thrombosis (McConnell et al., 2015, PMID 26379556; Shettigar et al., 2016, PMID 26908229), and knock-out tadpoles with severe DCM and almost imperceptible cardiac motion that the authors failed to rescue (Landim-Vieira, 2019, PMID 32038292). Previously mentioned human evidence in this last study (compound heterozygosity of p.D145E and p.D132N) was judged insufficient to demonstrate the existence of TNNC1-related autosomal recessive DCM. TNNC1 has also been curated by the Hereditary Cardiovascular Disease gene curation expert group for hypertrophic cardiomyopathy (Definitive, 09/13/2023) and the Arrhythmogenic Right Ventricular Cardiomyopathy gene curation expert group for ARVC (No known disease relationship, 09/13/2019). In summary, there is strong evidence to support the relationship between TNNC1 and autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. In conclusion, TNNC1 is definitively associated with DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on July 10, 2020 (SOP Version 7). This written summary was updated on 04/18/2025 and approved by the DCM GCEP on 05/30/2025.