Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NIPBL : Cornelia de Lange syndrome

HGNC:28862 | MONDO_0016033
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
6
6
Tonkin ET et al. 2004 Jun (PMID:15146185);
Proband with predicted or proven null variant 1.5 0-2 10 10.5 10
Tonkin ET et al. 2004 Jun (PMID:15146185); Krantz ID et al. 2004 Jun (PMID:15146186);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
1
1
Krantz ID et al. 2004 Jun (PMID:15146186);
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
2
Protein Interaction 0.5 0 - 2 1
Bermudez VP et al. 2012 Jun 12 (PMID:22628566);
Expression 0.5 0 - 2 1
Tonkin ET et al. 2004 Jun (PMID:15146185); Krantz ID et al. 2004 Jun (PMID:15146186);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4 4
Kawauchi S et al. 2009 Sep (PMID:19763162); Wu Y et al. 2015 Nov (PMID:26544867); Muto A et al. 2014 Sep (PMID:25255084);
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) 6

 


 

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 12 6 18 YES
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)
Definitive
06/15/2018
EXPERT CURATION (DATE)
Definitive
06/20/2018
EVIDENCE SUMMARY
The NIPBL gene has been associated with autosomal dominant Cornelia de Lange syndrome in over 12 probands in 2 curated publications. NIPBL was first associated with this disease in humans in 2004 (Krantz et al 2004, Tonkin et al 2004). Variants in this gene generally occur de novo. The mechanism for disease is known to be loss of function. 243 unique variants have been classified as Pathogenic in ClinVar, 193 of which are frameshift, nonsense or consensus splice changes. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by expression, protein interactions and animal models that recapitulate the human disease. In summary, NIPBL is definitively associated with autosomal dominant Cornelia de Lange syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.