Gene Validity Classification Summary

Gene/Disease Pair:

MCM2 : autosomal dominant nonsyndromic deafness 70

MONDO:0014853 | ORPHA:90635 | OMIM:616968
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
0.00
0
Proband with predicted or proven null variant 1.5 0-2 10 0.00 0
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
1.00
1
Gao J et al. 2015 (PMID:26196677);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
0.00
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
0.00
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
1.00
1  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
Gao J et al. 2015 (PMID:26196677);
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
0.00
Aggregate Variant Analysis 0-6
0.00
Total Genetic Evidence Points (Maximum 12) 2
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
0.00
0.5
Protein Interaction 0.5 0 - 2 0.00
Expression 0.5 0 - 2 0.50
Gao J et al. 2015 (PMID:26196677);
Functional Alteration Patient cells 1 0 - 2 2
0.00
0.5
Non-patient cells 0.5 0 - 1 0.50
Gao J et al. 2015 (PMID:26196677);
Models Non-human model organism 2 0 - 4 4 0.00 0
Cell culture model 1 0 - 2 0.00
Rescue Rescue in human 2 0 - 4
0.00
Rescue in non-human model organism 2 0 - 4
0.00
Rescue in cell culture model 1 0 - 2 0.00
Rescue in patient cells 1 0 - 2 0.00
Total Experimental Evidence Points (Maximum 6) 1

 


 

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 1 3 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
10/18/2016
EXPERT CURATION (DATE)
LIMITED
03/29/2017
The MCM2 gene has been associated with ADNSHL in 1 probands in 1 publication. 1 unique variant (missense) has been reported in humans, and the variant in this gene segregated with disease in 8 additional family members. MCM2 was first associated with this disease in humans in 2015 (Gao et al.). This gene-disease association is supported by its expression in guinea pig cochlea and the increase in apoptotic activity reported by Gao et al. resulting from variation induced by the human p.R44C variant in HEK293 cells. While this indicates the impact of the variant on the protien, this change in the apoptotic pathway's relation to auditory pathways is not clear. 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. This classification was approved by the ClinGen Hearing Loss Working Group on 3/29/2017.