Gene Validity Classification Summary

Gene/Disease Pair:

ILDR1 : nonsyndromic genetic deafness

HGNC:28741 | MONDO_0019497
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 5
10
10
Borck G et al. 2011 Feb 11 (PMID:21255762); Diaz-Horta O et al. 2012 Nov 30 (PMID:23226338); Babanejad M et al. 2012 Oct (PMID:22903915); Yan D et al. 2016 Aug (PMID:27344577);
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 5 1
Borck G et al. 2011 Feb 11 (PMID:21255762);
Total Summed LOD Score 5    
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) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2 1 0.5
Sang Q et al. 2015 Mar 27 (PMID:25819842);
Expression 0.5 0 - 2 3 1.5
Borck G et al. 2011 Feb 11 (PMID:21255762); Higashi T et al. 2013 Feb 15 (PMID:23239027); Sang Q et al. 2015 Mar 27 (PMID:25819842);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 6 4
Higashi T et al. 2015 Mar 30 (PMID:25822906); Sang Q et al. 2015 Mar 27 (PMID:25819842); Sang Q et al. 2014 Dec 1 (PMID:24990150);
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) 6

 


 

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 6 18 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
EXPERT CURATION (DATE)
Definitive
11/21/2017
EVIDENCE SUMMARY
The ILDR1 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/20/2017. This association was made using case-level data and experimental data. At least 13 variants (missense, nonsense, frameshift, splice site) have been reported in humans. ILDR1 was first associated with this disease in humans as early as 2011 (Borck et al.). Association is seen in at least 15 probands in 4 publications (21255762, 23226338, 22903915, 27344577). Variants in this gene segregated with disease in more than 4 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (18 pts.) has been reached. The mechanism for disease is biallelic LOF (21255762, 23226338, 22903915, 27344577, 25819842, 24990150). This gene-disease association is supported by mouse and zebrafish models as well as expression and protein interaction studies (21255762, 23239027, 25822906, 25819842, 24990150). In summary, ILDR1 is definitively associated with autosomal recessive nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 11/21/2017.