TNNC1 was first reported in relation to hypertrophic cardiomyopathy (HCM) in humans in 2001 (Hoffman et al, PMID 11385718). Over 21 probands in 12 publications have been published (Hoffman et al, 2001, PMID 11385718; Landstrom et al, 2008, PMID 18572189; Chung et al, 2011, PMID 21262074; Parvatiyar, 2012, PMID 22815480; Jaafar et al, 2015, PMID 26779504; Mademont-Soler I, et al., 2017, PMID: 28771489; Viswanathan SK, et al., 2017, PMID: 29121657; Robyns T, et al., 2017, PMID: 29255176; Jääskeläinen P, et al., 2019, PMID: 30775854; Cabrera Borrego E, et al., 2020, PMID: 34317385; Chung H, et al., 2021, PMID: 33658040; Alves-Pinto R, et al., 2022, PMID: 34488226). At least eleven unique heterozygous variants (10 missense, 1 truncating) with some evidence to support their pathogenicity and segregation in three families have been reported. One variant, p.Asn144Asp, has been seen 23 times in HCM probands with no other genetic cause, with segregation to 12 affected relatives (personal communication, Tomas Robyns UZ Leuven). The mechanism of disease is unknown. The gene-disease relationship is supported by in vitro functional studies, animal models, and interactions with TNNI3 and TNNT2. Variants in TNNC1 have also been reported in association with dilated cardiomyopathy (DCM), left ventricular noncompaction (LVNC), and restrictive cardiomyopathy (RCM). TNNC1 was shown to have a definitive gene-disease relationship with DCM by the ClinGen DCM Gene Curation Expert Pane (GCEP). The relationship of TNNC1 with LVNC and RCM has not been evaluated. The relationship between TNNC1 and autosomal dominant hypertrophic cardiomyopathy was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy GCEP on November 1, 2016 and found to have a moderate classification. It was re-evaluated on September 13, 2023. As a result of this recuration, the classification changed from the original Moderate to Definitive.
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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