NSUN2 was first reported in relation to autosomal recessive RASopathies in 2012 (Martinez et al., PMID 22577224). At least 2 variants (e.g. frameshift, splice site) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, and experimental data but only the mouse model supporting this association could be scored (PMIDs: 24102521, 22144916, 22577224). Variants in this gene have been reported in at least 2 probands in 2 publications (PMIDs 22577224, 24102521). Variants in this gene segregated with disease in 2 additional family members. This gene-disease association is supported by a mouse model indicating that homozygous deletion of the NSUN2 gene caused short stature and craniofacial anomalies (PMIDs: 22144916). However, the patients reported with NSUN2 variants did not possess convincing clinical features consistent with Noonan syndrome, despite the reports from Fahiminiya et al. 2014 suggesting that the condition was Noonan-like. Therefore, using the expert judgment of the ClinGen RASopathy Gene Curation Expert Panel these cases were not scored. In summary, the relationship between NSUN2 and autosomal recessive RASopathies is disputed. More evidence is needed to either support or refute the role NSUN2 plays in this disease. Additionally, this gene will be separately assessed by the ClinGen ID/Autism Gene Curation Expert Panel for complex neurodevelopmental disorder. This classification was approved by the ClinGen RASopathy Gene Curation Expert Panel on 2/4/2019 (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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