ClinVar Genomic variation as it relates to human health

This sequence change falls in intron 2 of the BCKDHA gene. It does not directly change the encoded amino acid sequence of the BCKDHA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs398123497, gnomAD 0.02%). This variant has been observed in individual(s) with maple syrup urine disease (PMID: 20431954). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 93352). Studies have shown that this variant results in an insertion of 7bp after exon 2 and introduces a premature termination codon (PMID: 20431954). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Variant summary: BCKDHA c.288+9C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Some computational tools predict a significant impact on normal splicing: Two predict the variant creates a canonical 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in an alternate transcript with a 7 nt insertion (Fernandez-Guerra_2010). The variant allele was found at a frequency of 5.2e-05 in 251128 control chromosomes. c.288+9C>T has been reported in the literature in individuals affected with Maple Syrup Urine Disease (Fernandez-Guerra_2010, Strauss_2020), and these individuals are reported as compound heterozygous, carrying other pathogenic/likely pathogenic variants. These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One classified it as uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.