Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

RPE65 : Leber Congenital Amaurosis/Retinitis Pigmentosa

ORPHA:65 | OMIM:204100
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
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 0.00 0
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0.00
0
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
5.50
Srilekha S et al. 2015 (PMID:26147992); Astuti GD et al. 2016 Jul (PMID:26626312); Hamel CP et al. 2001 Apr (PMID:11264131); Singh HP et al. 2009 Sep (PMID:19339744);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
7.00
Xu F et al. 2012 (PMID:22509104); Srilekha S et al. 2015 (PMID:26147992); Astuti GD et al. 2016 Jul (PMID:26626312); Hamel CP et al. 2001 Apr (PMID:11264131); Kondo H et al. 2004 Dec (PMID:15557452);
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
0.00
0  
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 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
1.00
2
Jin M et al. 2005 Aug 12 (PMID:16096063);
Protein Interaction 0.5 0 - 2 0.00
Expression 0.5 0 - 2 1.00
Li S et al. 2015 Aug (PMID:25752820);
Functional Alteration Patient cells 1 0 - 2 2
0.00
0
Non-patient cells 0.5 0 - 1 0.00
Models Non-human model organism 2 0 - 4 4 4.00 4
Pang JJ et al. 2005 Feb 28 (PMID:15765048); Aguirre GD et al. 1998 Oct 30 (PMID:9808841);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
2.00
Bennett J et al. 2016 Aug 13 (PMID:27375040); Russell S et al. 2017 Aug 26 (PMID:28712537); (Successful rescue of blindness in patients using gene therapy.)
Rescue in non-human model organism 2 0 - 4
2.00
Acland GM et al. 2001 May (PMID:11326284); Bemelmans AP et al. 2006 Oct (PMID:17032058);
Rescue in cell culture model 1 0 - 2 0.00
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
EXPERT CURATION (DATE)
DEFINITIVE
02/13/2018
Approved by experts at Massachusetts Eye and Ear Infirmary. Variants in the RPE65 gene have been seen in patients diagnosed with both retinitis pigmentosa and Leber congenital amaurosis. It is possible that some variants influence the onset of blindness, which lead to the characterization of two separate diseases, though a correlation has yet to be proven. Patients diagnosed with LCA often have congenital blindness, while patients diagnosed with RP have very variable, progressive blindness. Night blindness has been characterized in patients diagnosed with both diseases. After reviewing the published literature of patients diagnosed with either disease, there is no phenotype/genotype correlation; although there is a possible spectrum. The variant association with late onset RP is unknown.