Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

RAI1 : Smith-Magenis syndrome

HGNC:9834 | MONDO_0008434
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Intellectual Disability and Autism
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
Slager RE et al. 2003 Apr (PMID:12652298); Bi W et al. 2004 Nov (PMID:15565467); Girirajan S et al. 2005 Nov (PMID:15788730); Bi W et al. 2006 Nov 15 (PMID:17041942);
Proband with predicted or proven null variant 1.5 0-2 10 3 3
Bi W et al. 2004 Nov (PMID:15565467); Girirajan S et al. 2005 Nov (PMID:15788730);
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) 12
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
Williams SR et al. 2012 Jun 8 (PMID:22578325);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 2
Bi W et al. 2005 Apr 15 (PMID:15746153); Williams SR et al. 2012 Jun 8 (PMID:22578325); Huang WH et al. 2016 Oct 19 (PMID:27693255);
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) 2.5



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 12 2.5 14.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The RAI1 gene has been associated with Smith-Magenis syndrome using the ClinGen Validity Framework as of 9/3/2018. The affected individuals show intellectual disability, delayed speech, dysmorphic facial features, sleep disturbances, and behavioral problems. This disease association was made using case-level data and experimental data. At least 9 variants (missense, nonsense, and frameshift) were curated from four publications (PMID: 15565467, 17041942, 15788730, and 12652298). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. While a micro-deletion in short arm of chromosome 17 was first identified in individuals with Smith-Magenis syndrome, subsequent studies indicated that haploinsufficiency of RAI1 within the deletion region is responsible for most of the clinical manifestations. To date, 32 unique variants within RAI1 have been classified as Pathogenic in ClinVar. The gene-disease association is supported by mouse models and patient-derived cells. The experimental evidence collectively shows that RAI1 is critical for cognitive function (intellectual disability), craniofacial development (dysmorphic facial features), energy homeostasis (obesity), and circadian rhythm (sleep disturbances). In summary, RAI1 is definitively associated with Smith-Magenis syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.