Gene Validity Classification Summary

Gene/Disease Pair:

GSDME : autosomal dominant nonsyndromic deafness

HGNC:2810 | MONDO_0019587
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss 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
Proband with predicted or proven null variant 1.5 0-2 10 8 8
Van Laer L et al. 1998 Oct (PMID:9771715); Bischoff AM et al. 2004 Jan-Feb (PMID:14676472); Yu C et al. 2003 Nov (PMID:14559215); Chai Y et al. 2014 Aug (PMID:24933359); Cheng J et al. 2007 Nov (PMID:17868390); Nishio A et al. 2014 Mar (PMID:24506266);
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
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) 11
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1.5
Van Laer L et al. 1998 Oct (PMID:9771715); Hosoya M et al. 2016 Feb 26 (PMID:26915689); Op de Beeck K et al. 2011 Sep (PMID:21522185);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1.5 4
Gregan J et al. 2003 Jul 14 (PMID:12853124); Busch-Nentwich E et al. 2004 Feb (PMID:14736743); Van Rossom S et al. 2012 July 25 (PMID:22848872);
Cell culture model 1 0 - 2 2.5
Van Laer L et al. 2004 Jun (PMID:15173223); Op de Beeck K et al. 2011 Sep (PMID:21522185);
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) 5.5

 


 

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 11 5.5 16.5 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
07/19/2018
EXPERT CURATION (DATE)
Definitive
07/19/2018
EVIDENCE SUMMARY
The DFNA5 (GSDME) gene has been associated with autosomal dominant nonsyndromic hearing loss​ using the ClinGen Clinical Validity Framework as of 5/26/2017​. This association was made using case-level data only. At least 5​ variants shown to cause a skipping of exon 8 have been reported in humans. DFNA5​ was first associated with this disease in humans as early as 1998​ (Van Laer et al.​). Association is seen in at least 7 probands in 6​ publications (9771715, 14676472, ​14559215, 24933359, 17868390, 24506266). Variants in this gene segregated with disease in 155 additional family members. The mechanism for disease is a heterozygous gain of function, as evidenced by several cell culture model systems (Gregan 2003, Van Laer 2004, Op de Beeck 2011, Van Rossom 2012), that results in an increase in apoptosis. In summary, DFNA5​ is definitively associated with autosomal dominant 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.