Gene Validity Classification Summary

Gene/Disease Pair:

OSBPL2 : nonsyndromic genetic deafness

HGNC:15761 | MONDO_0019497
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss EP
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
Proband with predicted or proven null variant 1.5 0-2 10 2 3 3
Xing G et al. 2015 Mar (PMID:25077649); Thoenes M et al. 2015 Feb 10 (PMID:25759012);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
0
0
Xing G et al. 2015 Mar (PMID:25077649);
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 3 3  
Candidate gene sequencing 2.11 1
Thoenes M et al. 2015 Feb 10 (PMID:25759012);
Exome/genome or all genes sequenced in linkage region 7.22 1
Xing G et al. 2015 Mar (PMID:25077649);
Total Summed LOD Score 9.33    
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) 6
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Xing G et al. 2015 Mar (PMID:25077649); Thoenes M et al. 2015 Feb 10 (PMID:25759012);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
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 6 1 7 NO
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
10/05/2018
EXPERT CURATION (DATE)
Moderate
05/16/2017
EVIDENCE SUMMARY
The OSBPL2 gene has been associated with autosomal dominant nonsyndromic hearing loss (ADNSHL) using the ClinGen Clinical Validity Framework as of 10/17/2016. This association was made using case-level data and expression data. At least 3 probands with 3 unique variants (missense, frameshift) have been reported in humans, and variants in this gene segregated with disease in 31 additional family members in 2 publications (PMID: 25077649, 25759012). OSBPL2 was first associated with this disease in humans in 2015 (Xing et al.). The two LOF variants that have been associated with ADNSHL suggest that the mechanism for disease is haploinsufficiency. This gene-disease association is supported by expression studies (PMID: 25077649, 25759012). In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss Working Group on 5/16/2017.