Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PAK3 : X-linked syndromic intellectual disability

HGNC:8592 | MONDO_0020119
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Intellectual Disability and Autism
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
1
1
Hertecant J et al. 2017 Apr (PMID:28126652);
Proband with predicted or proven null variant 1.5 0-2 10 3 3
Allen KM et al. 1998 Sep (PMID:9731525); Rejeb I et al. 2008 Nov (PMID:18523455);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
2.2
2.2
Muthusamy B et al. 2017 May (PMID:28481730); Bienvenu T et al. 2000 Aug 14 (PMID:10946356); Gedeon AK et al. 2003 Aug 1 (PMID:12884430); Peippo M et al. 2007 Oct 15 (PMID:17853471); Magini P et al. 2014 Jul 1 (PMID:24556213); Horvath GA et al. 2018 Jan (PMID:29246092); McMichael G et al. 2015 Feb (PMID:25666757);
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
3
3  
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 Points PMIDs/Notes
Points/Study Max Total 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) 9.2
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2 0.5
Allen KM et al. 1998 Sep (PMID:9731525);
Expression 0.5 0 - 2 1
Allen KM et al. 1998 Sep (PMID:9731525);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 1
Allen KM et al. 1998 Sep (PMID:9731525); Magini P et al. 2014 Jul 1 (PMID:24556213); Kreis P et al. 2007 Jul 20 (PMID:17537723);
Models Non-human model organism 2 0 - 4 4 1.5 2.5
Meng J et al. 2005 Jul 13 (PMID:16014725);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
1
Magini P et al. 2014 Jul 1 (PMID:24556213);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 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 9.2 5 14.2 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
08/15/2018
EXPERT CURATION (DATE)
Definitive
08/15/2018
EVIDENCE SUMMARY
The PAK3 gene has been associated with X-linked syndromic intellectual disability using the ClinGen Clinical Validity Framework as of 07/26/2018 . This association was made using case-level and experimental data. At least 10 variants (missense, nonsense, frameshift and a large deletion) have been reported in humans. PAK3 was first associated with this disease in humans as early as 1998 (Allen et al.). Summary of Case Level Data: 11.2 points. Association is seen in at least 10 probands in 10 publications (9731525, 10946356, 12884430, 17853471, 18523455, 24556213, 25666757, 27753653, 28481730, 28126652). Variants in this gene segregated with disease in 33 additional family members. This gene-disease association is supported by expression studies, in vitro functional assays and animal models. In summary, PAK3 is definitively associated with X-linked syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Autism and Intellectual Disability Working Group on 7/31/2018.