Gene Validity Classification Summary

Gene/Disease Pair:

HARS2 : Perrault syndrome 2

HGNC:4817 | MONDO_0013972
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
1.5
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
1.5
Pierce SB et al. 2011 Apr 19 (PMID:21464306); Lerat J et al. 2016 Dec (PMID:27650058);
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing 3.16 1
Pierce SB et al. 2011 Apr 19 (PMID:21464306);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.16    
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
Nishio SY et al. 2017 May (PMID:28263850);
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 1.5 1.5
Pierce SB et al. 2011 Apr 19 (PMID:21464306);
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

 


 

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 4.5 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
11/27/2018
EXPERT CURATION (DATE)
Limited
05/15/2018
EVIDENCE SUMMARY
The relationship between HARS2 and autosomal recessive Perrault syndrome was evaluated using the ClinGen Clinical Validity Framework as of 11/20/2017. Variants in HARS2 were first reported in humans with this disease as early as 2011 (Pierce et al.). At least 3 missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 3 probands in 2 publications (21464306, 27650058). Variants in this gene segregated with disease in 4 additional family members. Experimental evidence from S. cerevisiae and C. elegans models provide some evidence of the gene-disease association. 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 5/15/2018.