There have been two studies suggesting that A2ML1 can cause a RASopathy phenotype. Both Vissers et al. 2015 and van Trier et al. 2015 have identified variants in A2ML1 in patients with Noonan syndrome (NS). However, none of these variants could be scored due to their high frequency in the general population, lack of functional impact, or lack of segregation with disease (gnomad.broadinstitute.org, (van Trier et al., 2015; Vissers et al., 2015). As a result, no convincing genetic evidence has been published to associate the A2ML1 gene with RASopathies. However, there is a knock-in zebrafish model that developed cardiac and craniofacial defects similar to those caused by other RASopathy variants (Vissers et al., 2015). The association between A2ML1 and Noonan syndrome remains Disputed. The ClinGen RASopathy Expert Panel found no evidence associating A2ML1 with cardiofaciocutaneous syndrome, Costello syndrome, NS with loose anagen hair or NS with multiple lentigines. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 6/7/18 (SOP Version 5).
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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