Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PTCHD1 : non-syndromic X-linked intellectual disability

HGNC:26392 | MONDO_0019181
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
4
4
Chaudhry A et al. 2015 Sep (PMID:25131214); Farwell KD et al. 2015 Jul (PMID:25356970);
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
3
3
Chaudhry A et al. 2015 Sep (PMID:25131214); Grozeva D et al. 2015 Dec (PMID:26350204);
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
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) 7
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
0
0.5
Noor A et al. 2010 Sep 15 (PMID:20844286);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.5
Noor A et al. 2010 Sep 15 (PMID:20844286); Wells MF et al. 2016 Apr 7 (PMID:27007844);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 2
Wells MF et al. 2016 Apr 7 (PMID:27007844);
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) 2.5

 


 

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 7 2.5 9.5 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)
Moderate
09/17/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Definitive
09/17/2018
REASON(S) FOR CHANGE
PMID 25131214: Three affected patients (from families F, I, and N) described in this publication had large deletions involving only the PTCHD1 gene that could not be entered in the GCI, each contributing 1.5 points to the final genetic evidence score. PMID 28934986: One affected patient (patient 2) described in this publication had a large deletion encompassing exons 2-3 of the PTCHD1 gene that could not be entered in the GCI, contributing 1.5 points to the final genetic evidence score. PMID 20844286: Biochemical functional studies in this publication (evidence entered into GCI but not scored) awarded 0.25 points. Including the above evidence: Total genetic evidence points calculated = 12; Total experimental evidence points calculated = 2.75; Total awarded points = 14.75; Replication over time = Yes; Final classification = Definitive.
EXPERT CURATION (DATE)
Definitive
09/19/2018
EVIDENCE SUMMARY
Multiple independent reports of affected individuals with deleterious PTCHD1 variants, in addition to functional and mouse model evidence, support a compelling link between deleterious variants in PTCHD1 and X-linked intellectual disability.