ClinVar Miner

Submissions for variant NM_001918.5(DBT):c.1018-550A>G

gnomAD frequency: 0.00004  dbSNP: rs796052135
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668558 SCV000793180 uncertain significance Maple syrup urine disease 2017-07-31 criteria provided, single submitter clinical testing
Invitae RCV000668558 SCV001400045 pathogenic Maple syrup urine disease 2021-11-02 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the DBT gene. It does not directly change the encoded amino acid sequence of the DBT protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with maple syrup urine disease (PMID: 9621512). ClinVar contains an entry for this variant (Variation ID: 11946). Studies have shown that this variant results in an insertion between exons 8 and 9 and introduces a premature termination codon (PMID: 9621512). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668558 SCV002051382 likely pathogenic Maple syrup urine disease 2021-12-27 criteria provided, single submitter clinical testing Variant summary: DBT c.1018-550A>G is located at a deep intronic position, not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant creates a 5' donor site. The variant allele was found at a frequency of 3.3e-05 in 150962 control chromosomes (gnomAD v3.1 genomes dataset). c.1018-550A>G has been reported in the literature in a homozygous individual affected with Maple Syrup Urine Disease (Tsuruta_1998). The authors of this study reported experimental evidence and demonstrated that the level of the DBT protein was considerably decreased in patient derived LCLS, in addition, they found inclusion of intronic sequence in patient derived cDNA, which was predicted to result in a truncated protein. These findings were confirmed in an in vitro assay system, where generation of a pseudoexon was demonstrated, resulting in aberrant splicing in vitro (Tsuruta_1998). These data indicate that the variant is likely associated with disease. Two ClinVar submitters have assessed the variant since 2014,, and classified the variant as likely pathogenic or uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mendelics RCV000668558 SCV002519476 pathogenic Maple syrup urine disease 2022-05-04 criteria provided, single submitter clinical testing
OMIM RCV000012724 SCV000032959 pathogenic Intermediate maple syrup urine disease type 2 1998-01-01 no assertion criteria provided literature only

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