Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

AARS : undetermined early-onset epileptic encephalopathy

HGNC:20 | MONDO_0018614
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Epilepsy
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
3.5
Nakayama T et al. 2017 Oct (PMID:28493438);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
1.5
Simons C et al. 2015 Apr 2 (PMID:25817015);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1.5
Nakayama T et al. 2017 Oct (PMID:28493438);
Non-patient cells 0.5 0 - 1 1 0.5
Nakayama T et al. 2017 Oct (PMID:28493438);
Models Non-human model organism 2 0 - 4 4 1 0.5 0.5
Simons C et al. 2015 Apr 2 (PMID:25817015);
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 3.5 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
11/28/2018
EXPERT CURATION (DATE)
Limited
11/20/2018
EVIDENCE SUMMARY
The relationship between AARS and autosomal recessive Undetermined Early-onset Epileptic Encephalopathy was evaluated using the ClinGen Clinical Validity Framework as of 11/20/2018. Variants in AARS were first reported in humans with this disease as early as 2015 (Simons et al., PMID 25817015). At least 1 frameshift and 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 (PMID: 25817015, 28493438). Variants in this gene segregated with disease in 2 additional family members. This gene-disease association is supported by functional studies that show variants' affects on yeast growth and catalytic efficiency in patient-derived cell lines. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Epilepsy Working Group on 11/20/2018.