Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

RASA1 : Noonan syndrome

HGNC:9871 | 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
Proband with predicted or proven null variant 1.5 0-2 10 0 0
Macmurdo CF et al. 2016 Jun (PMID:26969842);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
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) 0
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
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

 

 

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 0 0 0 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)
No Classification
06/07/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
06/07/2018
REASON(S) FOR CHANGE
All patients reported to date have capillary malformations without additional features of a RASopathy that couldn't be explained by an alternate cause.
EXPERT CURATION (DATE)
Disputed
06/07/2018
EVIDENCE SUMMARY
There have been multiple reported cases both in the literature showing that RASA1 variants can cause cardiovascular anomalies such as capillary malformation-arteriovenous malformation syndrome (CM-AVM);(Ilari, Agosta, & Bacino, 2016; Macmurdo et al., 2016). These studies suggest that these patients may possess clinical features of NS. However, patients with additional phenotypes such as hypotonia and severe ID all possess secondary causes of disease apart from RASA1 variation. Therefore, there is no convincing genetic evidence that supports the association of RASA1 and NS. In fact, RASA1 should most likely only be associated with cardiovascular anomalies. RASA1’s association with NS is Disputed.