Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PRPS1 : phosphoribosylpyrophosphate synthetase superactivity

HGNC:9462 | MONDO_0010395
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Hearing Loss
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 9
Becker MA et al. 1995 Nov (PMID:7593598); Porrmann J et al. 2017 Oct (PMID:28742244); Moran R et al. 2012 Feb (PMID:22246954); Roessler BJ et al. 1993 Dec 15 (PMID:8253776); García-Pavía P et al. 2003 Jul (PMID:12847698);
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  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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) 3.75
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 3
Becker MA et al. 1995 Nov (PMID:7593598); Porrmann J et al. 2017 Oct (PMID:28742244); Ahmed M et al. 1999 Mar 12 (PMID:10066814);
Non-patient cells 0.5 0 - 1 1 0.5
Chen P et al. 2013 Jun (PMID:23509005);
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) 2



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 2 5.75 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The PRPS1 gene has been associated with X-linked phosphoribosylpyrophosphate synthetase superactivity using the ClinGen Clinical Validity Framework as of 7/5/2018. This association was made using Case-level and experimental data. At least 9 variants (GOF missense) have been reported in humans. The PRPP protein was first associated with this disease in humans as early as 1972 (Sperling et al.), however Roessler et al. first identified variants in the PRPS1 gene in 1993. Association is seen in at least 8 probands in 5 publications (PMID's: 7593598, 28742244, 22246954, 8253776, 12847698). Variants in this gene segregated with disease in 1 additional family member (PMID: 28742244). Of note, the crystal structure of this enzyme has been solved, which informs that functionally assessed, GOF missense variants are located in one of two allosteric sites in the protein (Chen et al. 2015). This gene-disease association is supported by functional assays that show that PRPS1 variants cause an overproduction of pyrimidines that leads to the hyperuricemia and gout phenotypes (PMID's: 7593598, 28742244, 23509005). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechansim between PRPS1's association with PRPS1-superactivity and CMTX5/XLNSHL/Arts syndrome which are caused by PRPS1 LOF missense variants. Further case-data is required to strengthen this curation, however the association between PRPS1 and PRPS1 deficiency disorders (CMTX5/XLNSHL/Arts syndrome) is Definitive. In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. These classifications were approved by the ClinGen Hearing Loss Working Group on 7/9/2018.