Gene Validity Classification Summary

Gene/Disease Pair:

GRHL2 : nonsyndromic genetic deafness

HGNC:2799 | 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
Peters LM et al. 2002 Nov 1 (PMID:12393799); Vona B et al. 2013 Aug (PMID:23813623);
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   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 6.41 2
Peters LM et al. 2002 Nov 1 (PMID:12393799); Vona B et al. 2013 Aug (PMID:23813623);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 6.41    
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) 4.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2 1 0.5
Han Y et al. 2011 Aug 15 (PMID:21610158);
Expression 0.5 0 - 2 2 1
Peters LM et al. 2002 Nov 1 (PMID:12393799); Hosoya M et al. 2016 Feb 26 (PMID:26915689);
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 1 3
Han Y et al. 2011 Aug 15 (PMID:21610158);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Han Y et al. 2011 Aug 15 (PMID:21610158);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4.5

 


 

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 4.5 4.5 9 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
10/03/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Strong
10/03/2018
REASON(S) FOR CHANGE
Ji et al. 2014 (25342930) proband 3 had an exon 5 deletion that was not able to be added to the curation but was scored as 1 point. Clinvar submission from Tuebingen https://www.ncbi.nlm.nih.gov/clinvar/variation/425447/: proband with dominant family history of HL, via personal communication NM_024915.3(GRHL2):c.801delG (p.Met267Ilefs) variant is scored as 1 point. Clinvar submission from Emory https://www.ncbi.nlm.nih.gov/clinvar/variation/289923/: personal communication; variant found in mother and 5 mo. child with HL NM_024915.3(GRHL2):c.1098+1G>A is scored as 1 point. Therefore, the final Genetic Score is 7.5 points and the experimental evidence is 4.5 points. Final Classification is STRONG
EXPERT CURATION (DATE)
Strong
01/16/2018
EVIDENCE SUMMARY
The GRHL2 gene has been associated with autosomal dominant non-syndromic hearing loss using the ClinGen Clinical Validity Framework as of 3/6/2017. This association was made using case-level data, animal models, expression studies, and protein interaction studies. At least 5 unique variants (frameshift, splice site, exon deletion) have been reported in humans. GRHL2 was first associated with this disease in humans as early as 2002 (Peters et al.​). Association is seen in at least 6 probands in 3 publications and 2 ClinVar SCV's (PMIDs: 12393799, 23813623, 25342930, SCV000575569.4, SCV000344371.3). Variants in this gene segregated with disease in 13 additional family members (PMIDs: 12393799, 23813623). The mechanism for disease is haploinsufficiency (PMID: 12393799, 23813623, 25342930). This gene-disease association is supported by a zebrafish transposon-mediated gene trap model and mRNA rescue, expression studies in the inner ear of mice and protein interaction studies showing GRHL2B's interaction with claudins. In summary, there is strong evidence to support the association between GRHL2 and autosomal dominant non-syndromic hearing loss. Additional literature reports in humans are needed to reach a definitive classification. This classification was approved by the ClinGen Hearing Loss Working Group on 1/16/2018.