Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NSUN2 : intellectual disability

HGNC:25994 | MONDO_0001071
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Intellectual Disability and Autism
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 6
Fahiminiya S et al. 2014 Aug (PMID:24102521); Martinez FJ et al. 2012 Jun (PMID:22577224); Abbasi-Moheb L et al. 2012 May 4 (PMID:22541559); Komara M et al. 2015 Nov (PMID:26055038);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
Khan MA et al. 2012 May 4 (PMID:22541562); Harripaul R et al. 2018 Apr (PMID:28397838); Yavarna T et al. 2015 Sep (PMID:26077850);
Segregation Evidence   Summed LOD Family Count 3 3  
Candidate gene sequencing 6.2 2
Abbasi-Moheb L et al. 2012 May 4 (PMID:22541559);
Exome/genome or all genes sequenced in linkage region 6.05 3
Martinez FJ et al. 2012 Jun (PMID:22577224); Abbasi-Moheb L et al. 2012 May 4 (PMID:22541559); Khan MA et al. 2012 May 4 (PMID:22541562);
Total Summed LOD Score 12.25    
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) 10.1
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 2 0.5
Chi L et al. 2013 Dec (PMID:23816522); Hussain S et al. 2015 Oct 31 (PMID:26582006);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 1.5 1.5
Blanco S et al. 2011 Dec (PMID:22144916); Abbasi-Moheb L et al. 2012 May 4 (PMID:22541559);
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) 2



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 10.1 2 12.1 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
All families that have been presented so far have been consanguineous with homozygous variants. Additionally the mouse model and fly models have not possessed a specific phenotypic spectrum. Therefore, all of the evidence has been downgraded and despite there being enough points for this classification to reach Strong/Definitive, experts have decided to downgrade this classification to Moderate.
NSUN2 was first reported in relation to autosomal recessive intellectual disability in 2012 (Abbasi-Moheb et al., Khan et al., Martinez et al., PMID 22541559, 22541562, 22577224 ). Patients with variants in this gene have presented with intellectual disability, dysmorphic facial features, developmental delay, short stature, and/or muscular hypotonia suggesting that alterations to this gene may cause a phenotypic spectrum of syndromic features. At least 8 variants (e.g. missense, splice site, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, experimental data. Variants in this gene have been reported in at least 9 probands in 7 publications (PMIDs 26055038, 22541559, 22577224, 24102521, 26077850, 28397838, 22541562). Variants in this gene segregated with disease in 11 additional family members. Based on the cases presented, the mechanism for disease is homozygous loss of function. Of note, patients with variants in NSUN2, some of which were scored here have been described to be Noonan-like (PMIDs 24102521, 22577224). These assertions have been assessed separately by the ClinGen RASopathy Gene Curation Expert Panel and their relationship with the RASopathies has been Disputed ( This gene-disease association is supported by a mouse model, a drosophila model and expression studies (PMIDs: 26582006, 22144916, 22541559). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen ID/Autism Gene Curation Expert Panel on 2/6/2019 (SOP Version 6).