Gene Validity Classification Summary

Gene/Disease Pair:

NDP : Norrie Disease

MONDO:0010691 | ORPHA:649 | OMIM:300658
Mode of Inheritance: X-linked inheritance (HP:0001427)
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
0.00
0
Proband with predicted or proven null variant 1.5 0-2 10 10.00 10
Berger W et al. 1992 Oct (PMID:1307245); Schuback DE et al. 1995 (PMID:7627181); Meindl A et al. 1992 Oct (PMID:1303264); Andarva M et al. 2018 Mar (PMID:28922694); Walker JL et al. 1997 (PMID:8990009); Smith SE et al. 2012 Aug (PMID:22786811);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
1.00
1
Rehm HL et al. 1997 (PMID:9143918); Sims KB et al. 1997 Apr (PMID:9109762);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
0.00
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
0.00
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
3.00
3  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
Walker JL et al. 1997 (PMID:8990009);
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
0.00
Aggregate Variant Analysis 0-6
0.00
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
0.00
0.5
Protein Interaction 0.5 0 - 2 0.00
Expression 0.5 0 - 2 0.50
Chen ZY et al. 1993 May (PMID:8314592);
Functional Alteration Patient cells 1 0 - 2 2
0.00
1
Non-patient cells 0.5 0 - 1 1.00
Xu Q et al. 2004 Mar 19 (PMID:15035989);
Models Non-human model organism 2 0 - 4 4 3.00 4
Berger W et al. 1996 Jan (PMID:8789439); Rehm HL et al. 2002 Jun 1 (PMID:12040033); Ohlmann A et al. 2005 Feb 16 (PMID:15716406);
Cell culture model 1 0 - 2 0.00
Rescue Rescue in human 2 0 - 4
0.00
Rescue in non-human model organism 2 0 - 4
2.00
Rescue in cell culture model 1 0 - 2 0.00
Rescue in patient cells 1 0 - 2 0.00
Total Experimental Evidence Points (Maximum 6) 5.5

 


 

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 12 5.5 17.5 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
03/23/2018
EXPERT CURATION (DATE)
DEFINITIVE
03/21/2018
Evidence Summary The association between the NDP gene and Norrie disease (ND) is well-characterized, with over 100 unique variants described in HGMD, including nonsense, missense, splice, and deletion variants reported in dozens of publications. Familial segregation data is readily available; only a subset are included in this curation. Experimental evidence includes several mouse models of disease and protein interaction studies highlighting NDP's role in FZD4 interaction and Wnt signaling. NOTE: In terms of X-linked intellectual disability, ND is incompletely penetrant. The main phenotype associated with ND is abnormal vascular development within the eye, and only ~50% of patients with ND exhibit intellectual disability