Gene Validity Curation

USH1C - nonsyndromic genetic deafness

Gene: USH1C (HGNC:12597)
Classification - 06/11/2018
Disease: nonsyndromic genetic deafness (MONDO_0019497)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Hearing Loss EP
Evidence Summary: The USH1C gene has been associated with ARNSHL in at least 5 probands in 5 publications. 5 unique variants (missense, frameshift, large deletion) have been reported in humans, and variants in this gene segregated with disease in 5 additional family members (PMID: 12107438, 9653658). However, several variants were not scored due to lack of evidence for pathogenicity (PMID: 12136232). USH1C was first associated with this disease in humans in 1998 (Jain et al.). This gene-disease association is supported by 2 mouse models with deletions in the USH1C gene who were deaf but lacked the retinal phenotype of Usher Syndrome I as well as 1 expression study which showed that the longer transcript including the PDZ domain (which is thought to be the region affected to cause NSHL) was only expressed in the ear and not the retina. However, the mouse model from Williams 2009 was not scored because Johnson 2003 found that the mice displayed retinal degeneration at 9 months in addition to circling behavior (PMID: 19324851, 14519688). In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association.
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 1
1.5
1.5
Ahmed ZM et al. 2002 Jun (PMID:12107438);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
0
Ouyang XM et al. 2002 Jul (PMID:12136232);
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing 4.4 1
Ahmed ZM et al. 2002 Jun (PMID:12107438);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 4.4    
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) 2.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Verpy E et al. 2000 Sep (PMID:10973247);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 2 2
Williams DS et al. 2009 Aug (PMID:19324851); Johnson KR et al. 2003 Dec 01 (PMID:14519688);
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) 2.5

 


 

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 2.5 2.5 5 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)
Limited
11/16/2018
EXPERT CURATION (DATE)
Limited
06/11/2018
EVIDENCE SUMMARY
The USH1C gene has been associated with ARNSHL in at least 5 probands in 5 publications. 5 unique variants (missense, frameshift, large deletion) have been reported in humans, and variants in this gene segregated with disease in 5 additional family members (PMID: 12107438, 9653658). However, several variants were not scored due to lack of evidence for pathogenicity (PMID: 12136232). USH1C was first associated with this disease in humans in 1998 (Jain et al.). This gene-disease association is supported by 2 mouse models with deletions in the USH1C gene who were deaf but lacked the retinal phenotype of Usher Syndrome I as well as 1 expression study which showed that the longer transcript including the PDZ domain (which is thought to be the region affected to cause NSHL) was only expressed in the ear and not the retina. However, the mouse model from Williams 2009 was not scored because Johnson 2003 found that the mice displayed retinal degeneration at 9 months in addition to circling behavior (PMID: 19324851, 14519688). In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association.