Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

DMGDH : dimethylglycine dehydrogenase deficiency

HGNC:24475 | MONDO_0011610
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
1.5
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
1.5
Moolenaar SH et al. 1999 Apr (PMID:10102904);
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) 1.5
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
0.5
0.5
Dolphin CT et al. 1997 Dec (PMID:9398858);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
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) 0.5

 

 

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 1.5 0.5 2 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
07/01/2019
EXPERT CURATION (DATE)
Limited
06/28/2019
EVIDENCE SUMMARY
The relationship between DMGDH and dimethylglycine dehydrogenase deficiency was evaluated using the ClinGen Clinical Validity Framework as of 4/23/19. A human with this disease was first reported in 1999 (Moolenaar et al; PMID: 10102904) with the variant being identified in 2001 (Binzak et al; PMID: 11231903). Only this one missense variant with functional evidence to support pathogenicity has been reported in humans. This gene-disease relationship is also supported by biochemical assays. In summary, there is limited evidence to support this gene-disease relationship mostly due to the lack of variants published in humans. 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 Aminoacidopathy Working Group on 06/28/19 (SOP Version 6).