Gene Validity Classification Summary

Gene/Disease Pair:

RAB39B : early-onset parkinsonism-intellectual disability syndrome

HGNC:16499 | MONDO_0010709
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Autism and Intellectual Disability EP
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
4
4
Ciammola A et al. 2017 Nov (PMID:28851564); Vissers LE et al. 2010 Dec (PMID:21076407);
Proband with predicted or proven null variant 1.5 0-2 10 6 6
Wilson GR et al. 2014 Dec 4 (PMID:25434005); Giannandrea M et al. 2010 Feb 12 (PMID:20159109); Ciammola A et al. 2017 Nov (PMID:28851564);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0.5
0.5
Lesage S et al. 2015 Jun (PMID:27066548);
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
Expression 0.5 0 - 2 0.5
Giannandrea M et al. 2010 Feb 12 (PMID:20159109);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 0.5
Mignogna ML et al. 2015 Mar 18 (PMID:25784538);
Models Non-human model organism 2 0 - 4 4
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
06/04/2018
EXPERT CURATION (DATE)
Definitive
06/04/2018
EVIDENCE SUMMARY
Multiple unrelated individuals reported in the literature with overlapping phenotypes and loss-of-function and/or de novo variants in RAB39B. Several large families with compelling segregation data. Early experimental data supports a role for the gene and its protein product in neurocognitive processes.