Gene Validity Classification Summary

Gene/Disease Pair:

PRPS1 : PRPS1 deficiency disorder

HGNC:9462 | MONDO_0100061
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Hearing Loss EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
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
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 14
7
7
Liu X et al. 2010 Jan (PMID:20021999); Kim SY et al. 2016 Nov (PMID:27886419); Gandía M et al. 2015 Jul (PMID:25785835); Robusto M et al. 2015 Jun (PMID:25182139); Kim HJ et al. 2007 Sep (PMID:17701900); Almoguera B et al. 2014 Dec 10 (PMID:25491489); Maruyama K et al. 2016 Nov (PMID:27256512);
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   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 12.27 6
Liu X et al. 2010 Jan (PMID:20021999); Robusto M et al. 2015 Jun (PMID:25182139); Kim HJ et al. 2007 Sep (PMID:17701900); Almoguera B et al. 2014 Dec 10 (PMID:25491489);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 12.27    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points 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) 8.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 4 1.5
Liu X et al. 2010 Jan (PMID:20021999); Pei W et al. 2016 Jul 18 (PMID:27425195); Almoguera B et al. 2014 Dec 10 (PMID:25491489);
Functional Alteration Patient cells 1 0 - 2 2 6
6
2
Liu X et al. 2010 Jan (PMID:20021999); Cui B et al. 2004 Apr (PMID:15240907); Kim SY et al. 2016 Nov (PMID:27886419); Robusto M et al. 2015 Jun (PMID:25182139); Almoguera B et al. 2014 Dec 10 (PMID:25491489); Maruyama K et al. 2016 Nov (PMID:27256512);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
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) 3.5

 


 

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 8.5 3.5 12 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
11/26/2018
EXPERT CURATION (DATE)
Definitive
07/09/2018
EVIDENCE SUMMARY
The PRPS1 gene has been associated with X-linked syndromic and non-syndromic hearin loss in (at least) 14 probands in 13 publications.14 unique variants (LOF missense) have been reported in humans, and variants in this gene segregated with disease in over 15 additional family members. PRPS1 was first associated with hearing loss in humans in 1988 (Becker et al.), however since then it has been found to be associated with syndromic hearing loss (Arts Syndrome, CMTX5) as well as purine and pyrimidine disorders. There is some understanding of the mechanisms by which missense variants cause each disorder due to structural analysis strengthened by crystal structures of the protein and its variants, however intrafamilial variation of phenotype makes it difficult to separate PRPS1 nonsyndromic and syndromic hearing loss. Loss of function has been found to cause DFN2, CMTX5, and Arts Syndrome, while PRPS1 superactivity, which leads to purine/pyrimidine disorders is caused by destabilization of the allosteric sites (de Brouwer et al. 2010). In summary, PRPS1 is definitively associated with syndromic/nonsyndromic X-linked sensorineural hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.