Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PET117 : Leigh syndrome

HGNC:40045 | MONDO_0009723
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Mitochondrial Diseases
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
Renkema GH et al. 2017 Jun (PMID:28386624);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
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) 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 1
Taylor NG et al. 2017 Feb 3 (PMID:27998984);
Protein Interaction 0.5 0 - 2 1 0.5
Taylor NG et al. 2017 Feb 3 (PMID:27998984);
Expression 0.5 0 - 2 1 0.5
Uhlén M et al. 2015 Jan 23 (PMID:25613900);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
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) 2



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 2.5 2 4.5 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between PET117 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 13, 2019. 2 articles were reviewed. PET117 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2017 (Renkema et al., PMID: 28386624). The variant reported in this patient is a nonsense variant leading to a premature stop codon. Complex IV deficiency is the disease mechanism for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in 1 proband with Leigh syndrome spectrum in 1 publication (PMID 28386624). This gene-disease association is further supported by the function of the gene product and interaction with another protein associated with Leigh syndrome spectrum. In summary, there is limited evidence to support the relationship between PET117 and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 13, 2019 (SOP Version 6).