Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GDI1 : non-syndromic X-linked intellectual disability

HGNC:4226 | 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
Proband with predicted or proven null variant 1.5 0-2 10 3 3
D'Adamo P et al. 1998 Jun (PMID:9620768); Strobl-Wildemann G et al. 2011 Dec (PMID:22002931); des Portes V et al. 1997 Apr (PMID:9106537);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0.6
0.6
D'Adamo P et al. 1998 Jun (PMID:9620768); Bienvenu T et al. 1998 Aug (PMID:9668174);
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
Strobl-Wildemann G et al. 2011 Dec (PMID:22002931);
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) 6.6
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max 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
1
Non-patient cells 0.5 0 - 1 1
Giannandrea M et al. 2010 Feb 12 (PMID:20159109); Bianchi V et al. 2012 Jan 23 (PMID:22291894);
Models Non-human model organism 2 0 - 4 4 4 4
D'Adamo P et al. 1998 Jun (PMID:9620768); Bianchi V et al. 2012 Jan 23 (PMID:22291894);
Cell culture model 1 0 - 2 0.5
D'Adamo P et al. 1998 Jun (PMID:9620768);
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) 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 6.6 5 11.6 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
05/24/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Moderate
05/24/2018
REASON(S) FOR CHANGE
Downgrading the segregation scoring to 2 due to detection method (Sanger Sequencing) of "candidate gene sequencing". Des Portes 1997 family MRX48 and Hamel 1996 family MRX41 showed good linkage analysis but it was not until D’Adamo 1998 that the mutation in both families was found to be in GDI1. This paper did not specify which individuals in these families were tested which led to varying segregation scores among curators for segregation data.
EXPERT CURATION (DATE)
Moderate
05/24/2018