NFATC1 was first reported in relation to autosomal dominant congenital heart disease in 2012 (Abdul-Sater et al., PMID:23226213). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: Bicuspid aortic valve, tricuspid atresia, atrioventricular septal defect, congenital heart disease, tetralogy of Fallot, and ventricular septal defect. Eight unique missense variants have been reported in eight probands in six publications (PMIDs: 23226213, 34363434, 25260786, 30007050, 34426522, 32859249). However, all the missense variants had high minor allele frequency (> 0.00001) in gnomAD v2.1.1 and very low REVEL score, so they were not scored. All of the experimental evidence was performed with these variants, and therefore was not scored (PMIDs: 30007050, 23226213, 34363434). In summary, the evidence supporting the relationship between NFATC1 and autosomal dominant congenital heart disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role NFATC1 plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 7/17/2023 (SOP Version 9).
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.