Gene Validity Classification Summary

Gene/Disease Pair:

A2ML1 : Noonan syndrome

HGNC:23336 | MONDO_0018997
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
0
0
Vissers LE et al. 2015 Mar (PMID:24939586);
Proband with predicted or proven null variant 1.5 0-2 10 0 0
van Trier DC et al. 2015 Jun (PMID:25862627);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0
0
Vissers LE et al. 2015 Mar (PMID:24939586);
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
0
Non-patient cells 0.5 0 - 1 0
Vissers LE et al. 2015 Mar (PMID:24939586);
Models Non-human model organism 2 0 - 4 4 0.5 0.5
Vissers LE et al. 2015 Mar (PMID:24939586);
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 0 0.5 0.5 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
06/07/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
06/07/2018
REASON(S) FOR CHANGE
None of the variants that are suggested to be NS variants are convincing enough to be scored. In fact, many would be classified as Benign.
EXPERT CURATION (DATE)
Disputed
06/07/2018
EVIDENCE SUMMARY
There have been two studies suggesting that A2ML1 can cause a RASopathy phenotype. Both Vissers et al. 2015 and van Trier et al. 2015 have identified variants in A2ML1 in patients with NS. However, none of these variants could be scored due to their high frequency in the general population, lack of functional impact, or lack of segregation with disease (gnomad.broadinstitute.org, (van Trier et al., 2015; Vissers et al., 2015). As a result, no convincing genetic evidence has been published to associate the A2ML1 gene with RASopathies. However, there was a knock-in zebrafish model that developed heart and craniofacial defects similar to those caused by other RASopathy variants(Vissers et al., 2015). The A2ML1:RASopathy association remains Disputed .