Gene Validity Classification Summary

Gene/Disease Pair:

CISD2 : Wolfram syndrome

HGNC:24212 | MONDO_0018105
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
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
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
6
6.25
Amr S et al. 2007 Oct (PMID:17846994); Mozzillo E et al. 2014 Jul 24 (PMID:25056293); Rondinelli M et al. 2015 Feb (PMID:25371195);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
0.25
Rouzier C et al. 2017 May 1 (PMID:28335035);
Segregation Evidence   Summed LOD Family Count 2 2  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 4.96 3
Amr S et al. 2007 Oct (PMID:17846994);
Total Summed LOD Score 4.96    
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) 8.25
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
0.5
0.5
Rouzier C et al. 2017 May 1 (PMID:28335035);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 2.5 2.5
Chen YF et al. 2009 May 15 (PMID:19451219); Wang CH et al. 2014 Sep 15 (PMID:24833725);
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 8.25 3 11.25 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
10/04/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Strong
10/04/2018
REASON(S) FOR CHANGE
Expert Review decided that the score of 11.25 needed additional information to gain a classification of Definitive.
EXPERT CURATION (DATE)
Strong
03/27/2018
EVIDENCE SUMMARY
The CISD2 gene has been associated with autosomal recessive Wolfram syndrome using the ClinGen Clinical Validity Framework as of 3/23/2018. This association was made using case-level data only. At least 4 variants (e.g. missense, splice-site, small deletion) have been reported in humans. CISD2 was first associated with this disease in humans as early as 2007 (Amr et al.). Five families have been identified in which a variant in CISD2 segregates with WFS (Amr et al. 2007, Mozzillo et al. 2014, Rondinelli et al. 2015). A mouse model has been created and several functional studies have been performed which show that LoF of the CISD2 gene leads to a phenotype similar to WFS or changes the behavior of the cells in which the variant protein is present (Chen et al. 2009, Amr et al. 2007, Tsai et al. 2015). In summary, there is strong evidence to support the association between CISD2 and autosomal recessive Wolfram syndrome. After Expert Review, it was decided that additional reports in humans are needed to reach a definitive classification. This classification was approved by the ClinGen Hearing Loss Working Group on 3/27/2018.