Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NSUN2 : RASopathy

HGNC:25994 | MONDO_0021060
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: RASopathy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count 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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 2
0
0
Fahiminiya S et al. 2014 Aug (PMID:24102521); Martinez FJ et al. 2012 Jun (PMID:22577224);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points 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 Count 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 1 0 0
Blanco S et al. 2011 Dec (PMID:22144916);
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
02/04/2019
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
02/04/2019
REASON(S) FOR CHANGE
The patients reported with NSUN2 variants did not possess convincing clinical features consistent with Noonan syndrome, despite the reports from Fahiminiya et al. 2014 suggesting that the condition was Noonan-like. Therefore, using the expert judgment of the ClinGen RASopathy Gene Curation Expert Panel these cases were not scored.
EXPERT CURATION (DATE)
Disputed
02/04/2019
EVIDENCE SUMMARY
NSUN2 was first reported in relation to autosomal recessive RASopathies in 2012 (Martinez et al., PMID 22577224). At least 2 variants (e.g. frameshift, splice site) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, and experimental data but only the mouse model supporting this association could be scored (PMIDs: 24102521, 22144916, 22577224). Variants in this gene have been reported in at least 2 probands in 2 publications (PMIDs 22577224, 24102521). Variants in this gene segregated with disease in 2 additional family members. This gene-disease association is supported by a mouse model indicating that homozygous deletion of the NSUN2 gene caused short stature and craniofacial anomalies (PMIDs: 22144916). However, the patients reported with NSUN2 variants did not possess convincing clinical features consistent with Noonan syndrome, despite the reports from Fahiminiya et al. 2014 suggesting that the condition was Noonan-like. Therefore, using the expert judgment of the ClinGen RASopathy Gene Curation Expert Panel these cases were not scored. In summary, the relationship between NSUN2 and autosomal recessive RASopathies is disputed. More evidence is needed to either support or refute the role NSUN2 plays in this disease. Additionally, this gene will be separately assessed by the ClinGen ID/Autism Gene Curation Expert Panel for complex neurodevelopmental disorder. This classification was approved by the ClinGen RASopathy Gene Curation Expert Panel on 2/4/2019 (SOP Version 5).