Gene Validity Classification Summary

Gene/Disease Pair:

NARS2 : nonsyndromic genetic deafness

HGNC:26274 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
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
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
0.5
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
0.5
Simon M et al. 2015 Mar (PMID:25807530);
Segregation Evidence   Summed LOD Family Count 3 3  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 5.1 1
Simon M et al. 2015 Mar (PMID:25807530);
Total Summed LOD Score 5.1    
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) 3.5
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
Simon M et al. 2015 Mar (PMID:25807530);
Functional Alteration Patient cells 1 0 - 2 2
0
Non-patient cells 0.5 0 - 1 1 0
Simon M et al. 2015 Mar (PMID:25807530);
Models Non-human model organism 2 0 - 4 4
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) 0.5

 


 

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 3.5 0.5 4 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
10/03/2018
EXPERT CURATION (DATE)
Limited
12/19/2017
EVIDENCE SUMMARY
The NARS2 gene has been associated with autosomal recessive nonsyndromic sensorineural hearing loss (ARNSHL) using the ClinGen Clinical Validity Framework as of 3/15/2017. This association was made using case-level data and experimental evidence only). At least 1 unique variant (missense) has been reported in humans. NARS2 was first associated with this disease in humans as early as 2015 (Simon et al.). Association is seen in at least 1 proband in 1 publications (Simon 2015 25807530). Variants in this gene segregated with disease in 5 additional family members. Of note, this gene has also been associated with Leigh syndrome (Simon 2015), Alpers syndrome (Sofou 2015), and mitochondrial disorder (Vanlander 2015, Wang 2016) and Perrault syndrome in the family described in Simon et al. 2015 could not be ruled out. This gene-disease association is supported by expression studies in human and mouse cochlea (Simon 2015). 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 12/19/2017.