Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

DBT : maple syrup urine disease

HGNC:2698 | MONDO_0009563
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 6
12
12
Lebo RV et al. 2000 Sep (PMID:10915611); Imtiaz F et al. 2017 Jun (PMID:28417071); Hou JW et al. 2016 Oct (PMID:24486081); Yang N et al. 2012 Aug (PMID:22727569);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
1.75
Tsuruta M et al. 1998 (PMID:9621512);
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
1
Blackburn PR et al. 2017 Sep 6 (PMID:28919799);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Herring WJ et al. 1991 Feb (PMID:1990841);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 4 4
Friedrich T et al. 2012 Mar (PMID:22046030); Jia F et al. 2016 Feb 5 (PMID:26683372); Homanics GE et al. 2006 Mar 31 (PMID:16579849);
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
11/16/2018
EXPERT CURATION (DATE)
Definitive
10/30/2018
EVIDENCE SUMMARY
The relationship between DBT and maple syrup urine disease (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of October, 2018. Variants in DBT were first reported in humans with the disease as early as 1991 (Herring et al., PMID: 1990841). At least 11 variants (missense, nonsense, frameshift, deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. About 20% of MSUD cases are attributed to variants in this gene (Strauss et al., 2013; PMID: 20301495). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (18 pts.) has been reached. In summary, DBT is definitively associated with autosomal recessive maple syrup urine disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoaciopathy Gene Curation Expert Panel on 10/30/18 (SOP Version 5).