ClinVar Miner

Submissions for variant NM_183050.4(BCKDHB):c.2T>C (p.Met1Thr)

dbSNP: rs940391887
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669039 SCV000793737 likely pathogenic Maple syrup urine disease 2017-08-29 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000669039 SCV003780396 pathogenic Maple syrup urine disease 2022-08-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 553562). Disruption of the initiator codon has been observed in individual(s) with maple syrup urine disease (PMID: 26257134, 31980395, 32515140, 33300147; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the BCKDHB mRNA. The next in-frame methionine is located at codon 71.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000669039 SCV005887493 likely pathogenic Maple syrup urine disease 2025-01-24 criteria provided, single submitter clinical testing Variant summary: BCKDHB c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream in-frame initiation codon is at codon 71. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 155290 control chromosomes. c.2T>C has been reported in the literature in at-least one compound heterozygous individual affected with Maple Syrup Urine Disease (example: Chen_2023). Other variants affecting the initiation codon, as well as missense variants upstream of codon 71, have been classified as pathogenic in ClinVar. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 37421976). ClinVar contains an entry for this variant (Variation ID: 553562). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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