Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

KDM5C : X-linked syndromic intellectual disability

HGNC:11114 | 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 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 1
2
2
Abidi FE et al. 2008 Dec (PMID:18697827);
Proband with predicted or proven null variant 1.5 0-2 10 4 6 6
Jensen LR et al. 2005 Feb (PMID:15586325); Abidi FE et al. 2008 Dec (PMID:18697827);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
0
0
Jensen LR et al. 2005 Feb (PMID:15586325);
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   Summed LOD Family Count 2.2 2.2  
Candidate gene sequencing 3.32 2
Abidi FE et al. 2008 Dec (PMID:18697827);
Exome/genome or all genes sequenced in linkage region 2.71 2
Jensen LR et al. 2005 Feb (PMID:15586325);
Total Summed LOD Score 6.03    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points 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) 10.2
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count 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 1
Iwase S et al. 2016 Feb 9 (PMID:26804915);
Models Non-human model organism 2 0 - 4 4 1 2 2
Iwase S et al. 2016 Feb 9 (PMID:26804915);
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) 3

 


 

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 10.2 3 13.2 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
10/11/2018
EXPERT CURATION (DATE)
Definitive
09/28/2018
EVIDENCE SUMMARY
The KDM5C gene has been associated with X-linked syndromic intellectual disability using the ClinGen Clinical Validity Framework as of 9/17/2018. This association was made using case-level and experimental data. At least 9 variants (missense, frameshift, splice-site variants) have been reported in humans. KDM5C was first associated with this disease in humans as early as 2005 (Jensen et al.). Association is seen in at least 9 probands in 2 publications (PMID:15586325,18697827). Variants in this gene segregated with disease in 30 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence has been reached. The mechanism for disease is loss of function. This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. In summary, KDM5C is definitively associated with X-linked syndromic intellectual disability. This curation was approved by the Autism and Intellectual Disability Gene Curation Expert Panel on September 28, 2018.