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.
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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