MRAS was reported in relation to autosomal dominant Noonan syndrome as early as 2017 (Higgins et al., PMID: 28289718). At least 4 unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Four variants in this gene have been reported in at least 6 probands in 4 publications (PMIDs: 28289718, 31173466, 31108500, 34080768). This gene-disease association is supported by the interaction of MRAS with the Ras/MAPK pathway, which is associated with the Noonan Syndrome phenotype (PMID: 23875798), as well as interaction with SHOC2 and PPP1CB in the SHOC2-MRAS-PP1C holophosphatase complex (PMID: 35831509). The ClinGen RASopathy Expert Panel has assessed MRAS for associations with Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, and cardiofaciocutaneous syndrome, however no evidence was reported. 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 curation was approved by the ClinGen RASopathy Expert Panel on 8/27/20. This gene-disease pair was originally evaluated by the ClinGen RASopathy Expert Panel on 8/27/20. It was reevaluated on 12/14/22. As a result of this reevaluation, the classification did not change (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).
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