Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GRIA3 : X-Linked Syndromic Intellectual Disability

MONDO:0020119 | ORPHA:777 | OMIM:300104
Mode of Inheritance: X-linked recessive inheritance (HP:0001427)
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
0.00
Proband with predicted or proven null variant 1.5 0-2 10 1.00 1
Wu Y et al. 2007 Nov 13 (PMID:17989220); Chiyonobu T et al. 2007 Jul 1 (PMID:17568425); Guilmatre A et al. 2009 Sep (PMID:19736351);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
1.25
1.3
Wu Y et al. 2007 Nov 13 (PMID:17989220); Philips AK et al. 2014 Apr 11 (PMID:24721225);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
0.00
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
0.00
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
6.00
3  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
Philips AK et al. 2014 Apr 11 (PMID:24721225); Wu Y et al. 2007 Nov 13 (PMID:17989220);
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
0.00
Aggregate Variant Analysis 0-6
0.00
Total Genetic Evidence Points (Maximum 12) 5.3
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
0.00
0.5
Protein Interaction 0.5 0 - 2 0.00
Expression 0.5 0 - 2 0.50
Gécz J et al. 1999 Dec 15 (PMID:10644433);
Functional Alteration Patient cells 1 0 - 2 2
0.00
Non-patient cells 0.5 0 - 1 0.00
Models Non-human model organism 2 0 - 4 4 3.00 3
Meng Y et al. 2003 Jul 3 (PMID:12848940); Steenland HW et al. 2008 Mar (PMID:18312590); Sanchis-Segura C et al. 2006 Jan 25 (PMID:16436610); Adamczyk A et al. 2012 Apr 1 (PMID:22285418);
Cell culture model 1 0 - 2 0.00
Rescue Rescue in human 2 0 - 4
0.00
Rescue in non-human model organism 2 0 - 4
0.00
Rescue in cell culture model 1 0 - 2 0.00
Rescue in patient cells 1 0 - 2 0.00
Total Experimental Evidence Points (Maximum 6) 3.5

 


 

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 5.3 3.5 8.8 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
02/12/2018
EXPERT CURATION (DATE)
LIMITED
10/20/2017
The strength of this gene:disease association lies in 6 points for segregation. One of the families only has 2 affected males that goes through 4 carrier females. The family is also skewed for more females to males, and the only other male was not genotyped/phenotyped (Wu et al., 2007, M706T-IV:4 family/proband).