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. Three years must elapse from the first proposal of the relationship to reach a definitive classification. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 4/18/2025 (SOP Version 10).
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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