Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

BCKDHB : maple syrup urine disease type 1B

HGNC:987 | MONDO_0023692
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 5
Li X et al. 2018 Jun (PMID:29307017); Guo Y et al. 2015 Dec (PMID:26239723); Imtiaz F et al. 2017 Jun (PMID:28417071);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 7
Imtiaz F et al. 2017 Jun (PMID:28417071); Edelmann L et al. 2001 Oct (PMID:11509994);
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 2
Wynn RM et al. 2003 Oct 31 (PMID:12902323); 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
Non-patient cells 0.5 0 - 1 1 0.5
Chuang JL et al. 2004 Apr 23 (PMID:14742428);
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) 1.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 1.5 13.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between BCKDHB and maple syrup urine disease (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of September, 2018. Variants in BCKDHB were first reported in humans with this disease as early as 1991 (Nobukuni et al., PMID 2022752). At least 15 variants ( missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Approximately 35% of maple syrup urine disease cases can be attributed to pathogenic variants in BCKDHB (Strauss et al., 2006, PMID 20301495). 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 biochemical and in vitro assays. In summary, BCKDHB 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.