ClinVar Miner

Submissions for variant NM_001918.5(DBT):c.434-15_434-4del

gnomAD frequency: 0.00001  dbSNP: rs727503895
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000178857 SCV000231022 pathogenic not provided 2014-02-24 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001377734 SCV001575140 pathogenic Maple syrup urine disease 2023-12-28 criteria provided, single submitter clinical testing This sequence change falls in intron 4 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 present in population databases (rs727503895, gnomAD 0.009%). This variant has been observed in individual(s) with maple syrup urine disease (PMID: 9239422). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS4del[-15:-4]. ClinVar contains an entry for this variant (Variation ID: 166983). Studies have shown that this variant results in the insertion of 10 base pairs between exons 4 and 5 in the spliced mRNA and introduces a premature termination codon (PMID: 9239422). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV001377734 SCV004050172 pathogenic Maple syrup urine disease 2023-04-11 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003407575 SCV004107274 pathogenic DBT-related disorder 2023-09-18 criteria provided, single submitter clinical testing The DBT c.434-15_434-4del12 variant is predicted to result in an intronic deletion. This variant was reported in the compound heterozygous state with a second DBT variant in two individuals with maple syrup urine disease type II (described as IVS4del[-15:-4] in Chuang et al. 1997. PubMed ID: 9239422; Sajeev et al. 2021. PubMed ID: 34069211). In RT-PCR studies, this variant led to aberrant splicing (Chuang et al. 1997. PubMed ID: 9239422). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-100684306-GGTAACAAGGTAA-G). This variant is interpreted as pathogenic.
Baylor Genetics RCV004567173 SCV004190852 pathogenic Maple syrup urine disease type 1A 2023-11-14 criteria provided, single submitter clinical testing
GeneDx RCV000178857 SCV005325477 pathogenic not provided 2024-03-08 criteria provided, single submitter clinical testing Identified in trans with a second DBT variant in patients with MSUD (PMID: 9239422, 34069211); Non-canonical splice site variant demonstrated to result in loss of function (PMID: 9239422); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: Balasubramaniam2021[abstract], 9239422, 34069211)

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