ETS1 was first reported in relation to autosomal dominant Congenital Heart Disease in 2014 (Glessner et al., 2014; PMID: 25205790). The phenotype may be syndromic, with neurological and facial symptoms as well. Four variants (frameshift, nonsense) that have been reported in four probands in three publications (PMIDs: 25205790, 31160359, 32368696; 3Billion internal data) are included in this curation. The mechanism of pathogenicity appears to be loss of function, with multiple frameshift variants occurring at residue 349, and truncating the protein about 20 amino acids down. This gene-disease relationship is also supported by experimental evidence (a mouse model, functional alteration evidence, expression level evidence; PMIDs: 12915311, 19942620, 32810435). The mouse model has homozygous mutants showing the cardiac phenotype, as well as expression in the endocardium of healthy mice throughout the embryonic stage. Functional alteration indicates impaired function in iPSCs from patients with hypoplastic left heart syndrome. A chick embryo model shows cardiac expression. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date [11/21/2023 (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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