Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

BCKDHA : maple syrup urine disease type 1A

HGNC:986 | MONDO_0023691
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
Li X et al. 2015 Nov (PMID:26453840); Fern√°ndez-Lainez C et al. 2018 Aug (PMID:29673582); Georgiou T et al. 2009 Oct (PMID:19715473); 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 2
0.5
Imtiaz F et al. 2017 Jun (PMID:28417071);
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
0.5
1.5
Blackburn PR et al. 2017 Sep 6 (PMID:28919799);
Protein Interaction 0.5 0 - 2 1 1
Wynn RM et al. 1998 May 22 (PMID:9582350);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
2
2
Chuang JL et al. 1995 Mar (PMID:7883996);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Zhang B et al. 1990 Feb 15 (PMID:2303405);
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) 5.5

 


 

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 5.5 17.5 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
11/16/2018
EXPERT CURATION (DATE)
Definitive
09/14/2018
EVIDENCE SUMMARY
The relationship between BCKDHA and maple syrup urine disease (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of August, 2018. Variants in BCKDHA were first reported in humans with this disease as early as 1989 (Zhang et al., PMID: 2703538). At least 11 variants (missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene account for ~45% of MSUD cases (Strauss et al., 2013; PMID: 20301495). More cases are available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. BCKDHA encodes the E1 alpha subunit of the BCKAD complex and variants in the gene result in reduced activity of the complex. This gene-disease association is supported by in vitro studies and animal models. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on 9/14/18 (SOP Version 5).