Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

DLD : pyruvate dehydrogenase E3 deficiency

HGNC:2898 | MONDO_0009529
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Aminoacidopathy
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 3
6
12
Carrozzo R et al. 2014 Sep (PMID:25251739); Grafakou O et al. 2003 Oct (PMID:12925875); Hong YS et al. 1996 Dec (PMID:8968745);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 8
6.25
Liu TC et al. 1993 Jun 1 (PMID:8506365); Shany E et al. 1999 Aug 19 (PMID:10448086); Odièvre MH et al. 2005 Mar (PMID:15712224); Hong YS et al. 1997 Dec 31 (PMID:9540846); Cameron JM et al. 2006 Jul 15 (PMID:16770810); Quinonez SC et al. 2013 Jan (PMID:23290025); Shaag A et al. 1999 Jan 15 (PMID:9934985);
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.2 1
Odièvre MH et al. 2005 Mar (PMID:15712224);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.2    
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
1
Ambrus A et al. 2018 Jul (PMID:28579060);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Carrozzo R et al. 2014 Sep (PMID:25251739);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 0.5 0.5
Johnson MT et al. 1997 Dec 23 (PMID:9405644);
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) 2.5

 


 

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 2.5 14.5 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
03/08/2019
EXPERT CURATION (DATE)
Definitive
03/08/2019
EVIDENCE SUMMARY
The relationship between DLD and pyruvate dehydrogenase E3 deficiency (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of November 13, 2018. Variants in DLD were first reported in humans with this disease as early as 1993 (Liu et al., PMID: 8506365). At least 15 variants (missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of Case Level Data: 12 points. Variants in this gene have been reported in at least 11 probands in 10 publications. Variants in this gene segregated with disease in 3 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by in vitro functional assays and an animal model. In summary, DLD is definitively associated with autosomal recessive pyruvate dehydrogenase E3 deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on March 8th, 2019.