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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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