Gene Validity Curation

LRPPRC - Leigh syndrome

Gene: LRPPRC (HGNC:15714)
Classification - 12/19/2019
Disease: Leigh syndrome (MONDO_0009723)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Mitochondrial Diseases EP
Evidence Summary: The relationship between LRPPRC and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 9, 2019. The LRPPRC gene encodes an important post-transcriptional regulator of mitochondrial gene expression and coordinates mitochondrial translation. The LRPPRC gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2003 (PMID: 12529507). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three unique variants (including two founder variants) identified in 11 cases from three publications (PMIDs: 12529507, 26510951, 21266382). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, functional alteration in patient cells, animal models, and rescue in animal models (PMIDs: 27977873, 18853439, 20598281, 22821833, 27858754, 26380172). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 9, 2019 (SOP Version 7).
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 2
4
9.5
Oláhová M et al. 2015 Dec (PMID:26510951);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 9
5.5
Mootha VK et al. 2003 Jan 21 (PMID:12529507); Oláhová M et al. 2015 Dec (PMID:26510951); Debray FG et al. 2011 Mar (PMID:21266382);
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) 9.5
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
1.5
2
Rahman J et al. 2017 Jan (PMID:27977873);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Pontén F et al. 2008 Dec (PMID:18853439);
Functional Alteration Patient cells 1 0 - 2 2 2
2
2
Oláhová M et al. 2015 Dec (PMID:26510951); Burelle Y et al. 2015 Apr 2 (PMID:25835550);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 2 2.5
Ruzzenente B et al. 2012 Jan 18 (PMID:22045337); Baggio F et al. 2014 Dec 16 (PMID:25428350);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
0.5
Ruzzenente B et al. 2012 Jan 18 (PMID:22045337);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

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 9.5 6 15.5 YES
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)
Definitive
12/19/2019
EXPERT CURATION (DATE)
Definitive
12/19/2019
EVIDENCE SUMMARY
The relationship between LRPPRC and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 9, 2019. The LRPPRC gene encodes an important post-transcriptional regulator of mitochondrial gene expression and coordinates mitochondrial translation. The LRPPRC gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2003 (PMID: 12529507). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three unique variants (including two founder variants) identified in 11 cases from three publications (PMIDs: 12529507, 26510951, 21266382). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, functional alteration in patient cells, animal models, and rescue in animal models (PMIDs: 27977873, 18853439, 20598281, 22821833, 27858754, 26380172). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 9, 2019 (SOP Version 7).