Gene Validity Classification Summary

Gene/Disease Pair:

RPE65 : Retinitis pigmentosa

MONDO:0013425 | ORPHA:791 | OMIM:613794
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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
Proband with predicted or proven null variant 1.5 0-2 10 0.75 0.75
Simovich MJ et al. 2001 Aug (PMID:11462243);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Bowne SJ et al. 2011 Oct (PMID:21654732); Astuti GD et al. 2016 Jul (PMID:26626312); Galvin JA et al. 2005 Oct-Nov (PMID:16205573);
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
Bowne SJ et al. 2011 Oct (PMID:21654732);
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
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 3.75
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
Shin Y et al. 2017 Mar (PMID:28041994);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.50
Shin Y et al. 2017 Mar (PMID:28041994);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1.00
Shin Y et al. 2017 Mar (PMID:28041994);
Models Non-human model organism 2 0 - 4 4 1.00 1
Shin Y et al. 2017 Mar (PMID:28041994);
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) 3



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 3.75 3 6.75 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The gene-disease association for RPE65 and autosomal dominant retinitis pigmentosa has been classified as Moderate. A p.Asp477Gly variant in the RPE65 gene has been observed as heterozygous in four probands in the literature, all of Irish descent. Notably, the variant segregates in one family with 20 affected individuals, however there are four individuals carrying the variant without retinitis pigmentosa. The variability of onset, typically in the 2nd to 5th decade, may contribute. Three additional probands with the p.D477G variant have been reported internally at Massachusetts Eye and Ear Infirmary (MEEI). All affected individuals experienced progressive night vision problems starting the 2nd- 3rd decade and clinical evaluation was consistent with a clinical diagnosis of retinitis pigmentosa. All affected individuals reported a family history of night vision loss. Additional heterozygous probands with variants other than p.D477G have been observed in the RPE65 gene in patients diagnosed with LCA, however, there is no segregation information provided in these cases. A mouse model with a heterozygous knock-in p.D477G variant was generated by Shin et al. 2017, who suggest that the p.D477G variant suppresses isomerase activity in the wild-type RPE65 protein. While limitations of founder variant scoring conclude a total evidence point count of 6.75, an expert panel at MEEI has used expert opinion to increase the classification to Moderate.