ClinVar Miner

Submissions for variant NM_000709.4(BCKDHA):c.109-1G>A

dbSNP: rs2123253583
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001378292 SCV001575830 pathogenic Maple syrup urine disease 2022-12-07 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 of the BCKDHA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BCKDHA are known to be pathogenic (PMID: 16786533, 22593002). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1067117). Disruption of this splice site has been observed in individual(s) with maple syrup urine disease (Invitae). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001378292 SCV005205431 likely pathogenic Maple syrup urine disease 2024-06-03 criteria provided, single submitter clinical testing Variant summary: BCKDHA c.109-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251366 control chromosomes (gnomAD). To our knowledge, no occurrence of c.109-1G>A in individuals affected with Maple Syrup Urine Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1067117). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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