Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

DLG3 : non-syndromic X-linked intellectual disability

HGNC:2902 | 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
2
2
Tarpey P et al. 2004 Aug (PMID:15185169);
Proband with predicted or proven null variant 1.5 0-2 10 8 8
Zanni G et al. 2010 May (PMID:19795139); Tarpey P et al. 2004 Aug (PMID:15185169); Philips AK et al. 2014 Apr 11 (PMID:24721225); Tzschach A et al. 2015 Nov (PMID:25649377);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0.5
0.5
Kumar R et al. 2016 Nov (PMID:27222290);
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) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2 0.5
Chen BS et al. 2012 Nov 29 (PMID:23103165);
Expression 0.5 0 - 2
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
Cuthbert PC et al. 2007 Mar 7 (PMID:17344405);
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 12 2.5 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
EXPERT CURATION (DATE)
Definitive
08/24/2018
EVIDENCE SUMMARY
The DLG3 gene has been associated with non-syndromic X-linked intellectual disability using the ClinGen Clinical Validity Framework as of 2018 Jul 26. This association was made using case-level data only. At least 5 missense, 5 splicing, 2 small deletions, 3 small insertions have been reported in humans. DLG3 was first associated with this disease in humans as early as 2004 (Tarpey et al.). AND Summary of Case Level Data: 9 POINTS Association is seen in at least 9 probands in 5 publications (PMID: 15185169;19795139;24721225;25649377;2722290). Variants in this gene segregated with disease in 4-47 additional family members. For STRONG/DEFINITIVE genes (if applicable): More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function. (Tarpey et al 2004) Of note, this gene has also been implicated in Seizures and Epilepsy. These will be/have been assessed separately. EXPERIMENTAL EVIDENCE This gene-disease association is supported by animal models (mouse KO), Protein interactions et al.