NRAS

Inheritance Pattern: AD

Disease ID:MONDO:0007893

Submitter: ClinGen

There have been three studies published implicating NRAS with Noonan syndrome with multiple lentigines (NSML), however only one unique variant has been identified. The p.Gly60Glu variant has been identified in de novo cases, segregated in one family with disease, and individuals with unknown origin who possess clinical features of NSML (Ekvall et al., 2015; Kraoua et al., 2012). This variant has also been found in individuals without multiple lentigines with clinical features of NS (Cirstea et al., 2010). Of note, one individual with the p.Gly13Asp variant possessed the juvenile myelomonocytic leukemia phenotype in addition to clinical features of NSML (De Filippi et al., 2009). This case was not scored, but should be noted as a possible additional phenotype. The NRAS gene is also located in the Ras/MAPK pathway, which is associated with the NSML phenotype (Aoki et al., 2016; Rauen, 2013). In summary, the evidence supporting NRAS’s association with NSML is Limited, however the presence of multiple lentigines makes this evidence distinct from the other Noonan cases. Of note, NRAS has also been classified as Definitive in association with NS and as Limited in association with Costello syndrome and cardiofaciocutaneous syndrome. The ClinGen RASopathy Expert Panel found no evidence associating NRAS with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 5/30/18 (SOP Version 5).

Inheritance Pattern: AD

Disease ID:MONDO:0013186

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0013186

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0015280

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0015280

Submitter: ClinGen

Only two patients to date have been identified to have a cardiofaciocutaneous syndrome (CFC) diagnosis with NRAS variants (Altmuller et al., 2017). Of note, one patient had a complex phenotype that may be due to modifications from a 22q11.23 rearrangement, and the other patient presented with a p.T50I variant which has also been identified in patients with Noonan syndrome (NS) and no or mild developmental problems. This 11-year-old individual was noted to have mildly delayed motor and intellectual development with CFC facial features; however, variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of NS versus CFC. The NRAS gene is also located in the Ras/MAPK pathway, which is associated with the CFC phenotype (Aoki et al., 2016; Rauen, 2013). In summary, the evidence supporting the association between NRAS and CFC is Limited at this time. Of note, NRAS has also been classified as Definitive in association with NS and as Limited in association with NS with multiple lentigines and Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating NRAS with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).

Inheritance Pattern: AD

Disease ID:MONDO:0013186

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: ClinGen

There is a definitive association between alteration of the NRAS gene and Noonan syndrome (NS). The maximum amount of scorable genetic evidence has been published showing de novo as well as non-de novo variants occur in NRAS in patients with NS (Altmuller et al., 2017; Cirstea et al., 2010; Denayer et al., 2012; Runtuwene et al., 2011). The NRAS gene is also located in the Ras/MAPK pathway, which is associated with the NS phenotype and variants found in NS patients in this gene disrupt the RAS pathway function as demonstrated by zebrafish models (Aoki et al., 2016; Rauen, 2013; Runtuwene et al., 2011). Of note, NRAS has also been classified as Limited in association with Costello syndrome, cardiofaciocutaneous syndrome, and NS with multiple lentigines. The ClinGen RASopathy Expert Panel found no evidence associating NRAS with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 5/30/18 (SOP Version 5).

Inheritance Pattern: AD

Disease ID:MONDO:0009026

Submitter: ClinGen

One patient with clinical features of Costello syndrome (CS) has been identified in the literature to date (Altmuller et al., 2017). This patient carries a de novo p.Gly12Arg variant in NRAS and was assessed via WES. However, the age of evaluation may be a potential confounding factor of this diagnosis. The NRAS gene is also located in the Ras/MAPK pathway, which is associated with the CS phenotype (Aoki et al., 2016; Rauen, 2013). For now, the association remains as Limited, but will likely move to Disputed with time. Of note, NRAS has also been classified as Definitive in association with Noonan syndrome (NS) and as Limited in association with NS with multiple lentigines and cardiofaciocutaneous syndrome. The ClinGen RASopathy Expert Panel found no evidence associating NRAS with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).

Inheritance Pattern: AD

Disease ID:MONDO:0013186

Submitter: G2P