TNNT2: Hypertrophic cardiomyopathy. The TNNT2 gene has been associated with hypertrophic cardiomyopathy. TNNT2 was first associated with the disease in humans in 1994 (Thierfelder et al, 1994, PMID 8205619; Watkins et al, 1993, PMID 7981753; Watkins et al, 1995, PMID 7898523). Many unique variants, with varying levels of evidence to support their pathogenicity, have been reported in humans, as variants in TNNT2 account for ~5% of HCM cases (Cirino and Ho, 2014, PMID 20301725). Variants in this gene segregated with disease in at least 3 families (Thierfelder et al, 1994, PMID8205619). The mechanism for disease is likely dominant negative, as most mutations reported are missense variants. The gene-disease association is supported by the function of the gene product, animal models, and in vitro assays. In summary, TNNT2 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 Expert Panel on November 7th, 2017 using SOP version 5. This gene-disease relationship was updated and recurated by the HEreditary Cardiovascular GCEP on February 4, 2021.
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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