Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NRAS : Noonan syndrome with multiple lentigines

HGNC:7989 | MONDO_0007893
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: RASopathy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
De Filippi P et al. 2009 Dec (PMID:19775298); Kraoua L et al. 2012 Oct (PMID:22887781);
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Ekvall S et al. 2015 Oct 14 (PMID:26467218); Kraoua L et al. 2012 Oct (PMID:22887781);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 3
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2 0.5
Rauen KA et al. 2013 July 15 (PMID:23875798);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 0.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 3 0.5 3.5 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
There have been three studies published implicating NRAS with 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 NS with multiple lentigines (Ekvall et al., 2015; Kraoua et al., 2012). This variant has also been found in individual without multiple lentigines with clinical features of Noonan (Cirstea et al., 2010). Of note, one individual with the p.Gly13Asp variant possessed the juvenile myelomonocytic leukaemia 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.