Gene Validity Classification Summary

Gene/Disease Pair:

PQBP1 : Renpenning syndrome

HGNC:9330 | MONDO_0010653
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Autism and Intellectual Disability 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 13 11.5 10
Kalscheuer VM et al. 2003 Dec (PMID:14634649); Lenski C et al. 2004 Apr (PMID:15024694); Cossée M et al. 2006 Apr (PMID:16493439); Stevenson RE et al. 2005 May 1 (PMID:15782410);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
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 8.73 3
Kalscheuer VM et al. 2003 Dec (PMID:14634649); Lenski C et al. 2004 Apr (PMID:15024694); Stevenson RE et al. 2005 May 1 (PMID:15782410);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 8.73    
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) 11.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
2
Non-patient cells 0.5 0 - 1 3 2
Wang Q et al. 2013 Mar 15 (PMID:23512658); Mizuguchi M et al. 2014 Apr 30 (PMID:24781215); Zhang XY et al. 2017 Mar 1 (PMID:28073926);
Models Non-human model organism 2 0 - 4 4 2 1 1
Okuda T et al. 2003 Apr 1 (PMID:12651867); Ito H et al. 2015 Apr (PMID:25070536);
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
(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 11.5 3 14.5 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
11/09/2018
EXPERT CURATION (DATE)
Definitive
11/09/2018
EVIDENCE SUMMARY
The relationship between PQBP1 and X-linked Renpenning syndrome was evaluated using the ClinGen Clinical Validity Framework as of 9/27/18. Variants in PQBP1 were first reported in humans with this disease as early as 2003 (Kalscheuer et al.​). At least 7 frameshift variants, and additional missense and nonsense variants, have been reported in at least 9 male probands in 4 publications (PMIDs: 14634649, 15782410, 15024694, 16493439, 16740914, 20950397, 26411299, 25167861). Variants in this gene segregated with disease in 28 additional male family members, as well as unaffected female carriers. More evidence is available in the literature, but the maximum score for "predicted or proven null variants" for genetic evidence (10 pts) has been reached. This gene-disease association is supported by a conditional knockout mouse model with significantly reduced brain weight (PMID: 25070536) as well as functional studies demonstrating the pathogenicity of loss-of-function variants (PMIDs: 23512658, 24781215, 28073926). In summary, PQBP1​ is definitively associated with X-linked Renpenning syndrome. This classification was approved by the ClinGen Autism and Intellectual Disability Working Group on 11/7/2018.