Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

RAF1 : Noonan syndrome with multiple lentigines

HGNC:9829 | MONDO_0007893
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: RASopathy EP
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
2
2
Pandit B et al. 2007 Aug (PMID:17603483);
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
2
2
Pandit B et al. 2007 Aug (PMID:17603483); Carcavilla A et al. 2013 May (PMID:24775816); Kuburović V et al. 2011 Nov-Dec (PMID:22389993);
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) 4
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
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
0
Non-patient cells 0.5 0 - 1 0
Pandit B et al. 2007 Aug (PMID:17603483); Kobayashi T et al. 2010 Mar (PMID:20052757);
Models Non-human model organism 2 0 - 4 4 0
Cell culture model 1 0 - 2 0
Dhandapany PS et al. 2011 Jul (PMID:21440552);
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
(0-18)
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
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 4 0.5 4.5 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Limited
07/25/2018
EXPERT CURATION (DATE)
Limited
07/25/2018
EVIDENCE SUMMARY
There was only sufficient evidence in the literature for the RAF1:NSML association to be classified as Limited. Only two variants with supporting evidence for pathogenicity (one de novo) in the gene have been found in individuals with NSML (Carcavilla et al., 2013; Kuburovic, Vukomanovic, Carcavilla, Ezquieta-Zubicaray, & Kuburovic, 2011; Pandit et al., 2007). The RAF1 gene is also located in the Ras/MAPK pathway which is associated with the NSML phenotype (Aoki et al., 2016; Rauen, 2013).