Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

BRAF : Noonan syndrome

HGNC:1097 | MONDO_0018997
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
10
10
Razzaque MA et al. 2007 Aug (PMID:17603482); Sarkozy A et al. 2009 Apr (PMID:19206169);
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
0
0
Nyström AM et al. 2008 Aug (PMID:18456719); Sarkozy A et al. 2009 Apr (PMID:19206169); Lee BH et al. 2011 Dec (PMID:21784453); van Trier DC et al. 2016 Oct (PMID:27521173);
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) 10
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
Razzaque MA et al. 2007 Aug (PMID:17603482); Sarkozy A et al. 2009 Apr (PMID:19206169);
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
(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 10 0.5 10.5 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)
Moderate
07/24/2018
EXPERT CURATION (DATE)
Moderate
07/24/2018
EVIDENCE SUMMARY
There was sufficient genetic evidence in the literature for the BRAF:Noonan syndrome association to be classified as Moderate. However, variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of Noonan syndrome versus CFC. Additional genotype:phenotype correlations are necessary to solidify the association of BRAF with Noonan syndrome (Lee et al., 2011; Nystrom et al., 2008; Razzaque et al., 2007; Sarkozy et al., 2009; van Trier et al., 2016). The BRAF gene is also located in the Ras/MAPK pathway which is associated with the Noonan phenotype (Aoki, Niihori, Inoue, & Matsubara, 2016; Rauen, 2013)