Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

HRAS : Noonan syndrome-like disorder with loose anagen hair

HGNC:5173 | MONDO_0011899
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
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0
0
Bertola D et al. 2017 May (PMID:28371260);
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
07/25/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
07/25/2018
REASON(S) FOR CHANGE
An association has been suggested, but the claim by the authors was not strong.
EXPERT CURATION (DATE)
Disputed
07/25/2018
EVIDENCE SUMMARY
There has only been one study suggesting that patients with variants in HRAS have features consistent with Noonan-like syndrome with loose anagen hair (NS/LAH) (Bertola et al. 2017). This study identified five patients with sparse, loose anagen hair and p.Gly13Asp/p.Gly13Cys variants in HRAS. The authors note that no malignant tumors have been identified in these patients, however only one patient was older than 15yrs (28yrs) at the time of report, and it remains to be determined if the alteration of p.Gly13 in HRAS increases risk of tumor development. These patients did develop papillomata and vascular proliferation lesions as well as other features more consistent with CS, which led to the authors concluding that these cases expand the phenotypic spectrum of CS rather than support that HRAS causes NS/LAH. Therefore, the evidence for this association is Disputed.