Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CABP2 : nonsyndromic genetic deafness

HGNC:1385 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
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
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 3
5
5
Schrauwen I et al. 2012 Oct 5 (PMID:22981119); Bademci G et al. 2016 Apr (PMID:26226137); Picher MM et al. 2017 Feb 28 (PMID:28183797);
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
Exome/genome or all genes sequenced in linkage region 10.37 2
Schrauwen I et al. 2012 Oct 5 (PMID:22981119); Picher MM et al. 2017 Feb 28 (PMID:28183797);
Total Summed LOD Score 10.37    
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) 8
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
0.5
2
Picher MM et al. 2017 Feb 28 (PMID:28183797);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
Picher MM et al. 2017 Feb 28 (PMID:28183797); Cui G et al. 2007 Dec 15 (PMID:17947313); Yang T et al. 2016 Jan 25 (PMID:26809054);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 2 1
Schrauwen I et al. 2012 Oct 5 (PMID:22981119);
Models Non-human model organism 2 0 - 4 4 1 2 2
Picher MM et al. 2017 Feb 28 (PMID:28183797);
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) 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 8 5 13 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)
Strong
10/04/2018
EXPERT CURATION (DATE)
Strong
09/08/2017
EVIDENCE SUMMARY
The CABP2 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 9/6/2017. This association was made using case-level data only. At least 3 variants (splice-site and nonsense) have been reported in humans. CABP2 was first associated with this disease in humans as early as 2012 (Schrauwen et al.). Association is seen in at least 3 probands in 3 publications (22981119, 26226137, 28183797). Variants in this gene segregated with disease in at least 11 additional family members. This gene-disease association is supported by an animal model, expression studies, and biochemical function studies. In summary, there is strong evidence to support the association between CABP2 and autosomal recessive nonsyndromic hearing loss. While the classification reaches definitive, most of the evidence comes from the same group (Schrauwer et al., Picher et al.). Additional reports from different groups are needed to reach a definitive classification. This classification was approved by the ClinGen Hearing Loss​ Working Group on 9/8/2017.