Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PDHA1 : Leigh syndrome

HGNC:8806 | MONDO_0009723
Mode of Inheritance: X-linked inheritance (HP:0001417)
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 4
12
12
Marsac C et al. 1997 Jun (PMID:9187674); Lissens W et al. 1996 (PMID:8664900); Quintana E et al. 2010 May (PMID:20002461); Imbard A et al. 2011 Dec (PMID:21914562);
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
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) 12
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
2
Matthews PM et al. 1993 Jun (PMID:8498846);
Protein Interaction 0.5 0 - 2 1 1
Quintana E et al. 2009 Dec (PMID:19924563);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1.5
1.5
Shin HK et al. 2017 Nov (PMID:28918066);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 4 4
Pliss L et al. 2013 Jun 26 (PMID:23840713);
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) 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 12 6 18 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
04/08/2019
EXPERT CURATION (DATE)
Definitive
04/08/2019
EVIDENCE SUMMARY
The relationship between PDHA1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 25, 2019. 31 articles were reviewed. PDHA1 was first reported in relation to X-linked Leigh syndrome spectrum in 1993 (Matthews et al., PMID 8498846). Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in numerous probands in numerous publications (PMIDs 7887409, 8962591, 8664900, 9187674, 9671272, 10679936, 12621116, 15384102, 20002461, 21914562). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by the known biochemical function, protein interaction, functional studies in patient cell lines, and animal models. PDHA1 encodes the E1 alpha subunit of the pyruvate dehydrogenase complex (PDC). PDC catalyzes conversion of pyruvate into acetyl-CoA, thus is the link between glycolysis and the citric acid cycle. PDC deficiency leads to impaired energy metabolism. In summary, there is definitive evidence to support the relationship between PDHA1 and X-linked Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 25, 2019 (SOP Version 6).