Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MSRB3 : nonsyndromic genetic deafness

HGNC:27375 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
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 1
2
3
Ahmed ZM et al. 2011 Jan 07 (PMID:21185009);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
1
Ahmed ZM et al. 2011 Jan 07 (PMID:21185009);
Segregation Evidence   Summed LOD Family Count 3 3  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 14.66 1
Ahmed ZM et al. 2011 Jan 07 (PMID:21185009);
Total Summed LOD Score 14.66    
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) 6
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
0.5
1.5
Kwon TJ et al. 2014 Mar 15 (PMID:24191262);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Ahmed ZM et al. 2011 Jan 07 (PMID:21185009); Kwon TJ et al. 2014 Mar 15 (PMID:24191262);
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 2 4
Kwon TJ et al. 2014 Mar 15 (PMID:24191262);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Kim MA et al. 2016 Apr 10 (PMID:26649646);
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 6 5.5 11.5 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)
Strong
10/04/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Moderate
10/04/2018
REASON(S) FOR CHANGE
The Partners LMM has reported one case with profound congenital hearing loss and a novel homozygous splice variant in MSRB3.
EXPERT CURATION (DATE)
Moderate
11/15/2017
EVIDENCE SUMMARY
The MSRB3 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/25/17. This association was made using case-level data. At least one missense, nonsense and splice-site variant have been reported in humans. MSRB3 was first associated with this disease in humans as early as 2011 (Ahmed et al.​). Association is seen in at least 3 probands in 1 publication and unpublished clinical data (21185009, Partners LMM unpublished internal data). Variants in this gene segregated with disease in at least 20​ additional family members. This gene-disease association is supported by a null mouse model and a rescue in mice ears. In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss Working Group on 11/15/17.