TNNT2 was originally evaluated for DCM by ClinGen DCM GCEP on August 13, 2020. Evidence of the association of this gene with DCM was re-evaluated on 3/17/2025. 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.
TNNT2 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2000 (Kamisago et al., 2000, PMID 11106718) Human genetic evidence supporting this gene-disease relationship includes case-level data and segregation data. At least 10 variants (including missense and nonsense) have been reported in humans with DCM. Of note, the variant p.Lys210del has been reported in multiple unrelated families and been reported in at least one de novo case (Otten et al., 2002, PMID 20978592; Hershberger et al., 2009, PMID 20031601; Morgensen et al., 2004, PMID 15542288). It is considered a recurrent pathogenic variant. In addition, this gene-disease association is supported by animal models, expression studies, and in vitro functional assays. Towsend et al., first showed TNNT2 is expressed in the heart in 1994 (Towsend et al., 1994, PMID 8088824). Animal models include mouse models expressing the variant p.Lys210del which developed DCM and sudden cardiac death (Du et al., 2007, PMID 17556660). Additional evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence has been reached. TNNT2 has also been curated by the Hypertrophic Cardiomyopathy gene curation expert group for HCM (Definitive, 02/04/2021) and the Arrhythmogenic Right Ventricular Cardiomyopathy gene curation expert group for ARVC (No known disease relationship, 07/16/2019). In summary, TNNT2 is definitively associated with autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on August 13, 2020. (SOP Version 7). This written summary was updated on 3/17/2025 and approved by the DCM GCEP on 05/30/2025.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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