The Arg1038Gly missense variant in the NF1 gene causes a mild phenotype without neurofibromas

Abstract

Background Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by inactivating mutations of the NF1 gene. The wide allelic heterogeneity of this condition, with more than 3,000 pathogenic variants reported so far, is paralleled by its high clinical variability, which is observed even within the same family. The definition of genotype–phenotype correlations has been hampered by the complexity of the NF1 gene and, although a few exceptions have been recognized, the clinical course remains unpredictable in most patients. Methods Sequencing of NF1 in patients with cafè‐au‐lait spots identified the c.3112A>G variant. RNA analysis and a minigene assay were employed to investigate splicing. Results Here we report a novel genotype–phenotype correlation in NF1: the identification of the missense variant NM_000267.3:c.3112A>G p.(Arg1038Gly) in seven individuals from two unrelated families with a mild phenotype. All the patients manifest cafè‐au‐lait spots without neurofibromas or other NF1–associated complications, and Noonan syndrome features in most cases. The missense variant was not previously reported in available databases, segregates with the phenotype and involves a highly conserved residue. Both a minigene assay and patient's RNA analysis excluded an effect on splicing. Conclusion Our data support the correlation of the p.Arg1038Gly missense substitution with the cutaneous phenotype without neurofibromas or other complications. This finding may have relevant implications for patients and genetic counseling, but also to get insights into the function of neurofibromin.

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype–Phenotype Correlations in a Large Independent Cohort

“…A total of 309 NF1 patients were selected on the basis of the inclusion and exclusion criteria and included in the study; 255 were recruited from the authors' institutions (92 with OPG and 163 without OPG) and 54 were retrieved from the recent literature (40 with OPG and 14 without OPG) [33][34][35][36][37][38][39][40][41]. One hundred and thirty-two patients were included in the NF1 OPG group (61 females, 57 males; the sex of 14 patients retrieved from the literature was not reported) and 177 in the NF1 non-OPG group (91 females, 76 males; 10 unknown).…”

“…The only patients with the same mutation were patient number 144 in the series described by Tsipi et al [33] and patient number 10 in the series described by Ulusal et al [34] and, as these patients belonged to different cohorts and their mutation is known to be frequent, there is little likelihood of consanguineity. The two patients harbouring the same NF1 mutation and retrieved from the paper by Trevisson et al belonged to unrelated families [35].…”

“…The literature review allowed us to select 54 patients; there were more patients in the OPG group (40) than in the non-OPG group (14) [33][34][35][36][37][38][39][40][41].…”

In-silico Analysis of NF1 Missense Variants in ClinVar: Translating Variant Predictions into Variant Interpretation and Classification

“…Indeed, nearly half of variants deposited at ClinVar, and almost 90% of the missense changes are of uncertain significance. This scenario is further complicated by the milder phenotype observed in patients with either missense variants and/or in frame deletions and insertions [49][50][51].…”

Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders

“…Conversely, three variants in the first exon of NF1 causing RNA decay were only detectable by NGS analysis. Considering recently reported (and potential novel) genotype-phenotype correlations [15,16,18,52,65,66,67,68], evaluating the functional effect of genomic variants can have a positive impact on patients’ clinical follow-up.…”