Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

BRWD3 : X-linked syndromic intellectual disability

HGNC:17342 | 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 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 13.5 10
Field M et al. 2007 Aug (PMID:17668385); Tatton-Brown K et al. 2017 May 4 (PMID:28475857); Grotto S et al. 2014 Apr (PMID:24462886);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0.1
0.1
Field M et al. 2007 Aug (PMID:17668385);
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
0.5
Chen WY et al. 2015 Apr (PMID:25666827);
Protein Interaction 0.5 0 - 2
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 0.5 0.5
Chen WY et al. 2015 Apr (PMID:25666827);
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) 1

 


 

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 1 13 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
07/29/2018
EXPERT CURATION (DATE)
Definitive
09/20/2018
EVIDENCE SUMMARY
The literature presents strong genetic evidence of a gene-disease association with multiple unrelated individuals with overlapping phenotypes (intellectual disability, overgrowth, variable dysmorphic features) found to have loss-of-function and/or missense variants in BRWD3. In several cases, the BRWD3 variant was shown to segregate with disease in extended families. Emerging experimental evidence (primarily studies of drosophila) also supports a role for variants in BRWD3 as causative of syndromic ID. Note: Actual segregation points awarded for this curation is 2 but the change does not alter the final classification as definitive. Note: There are additional reported patients in the literature with loss-of-function and/or de novo variants in BRWD3. Inclusion of all reported patients was not necessary as the maximum points for genetic evidence had already been reached.