ClinVar Miner

Submissions for variant NM_001918.4(DBT):c.901C>T (p.Arg301Cys) (rs185492864)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079959 SCV000232151 pathogenic not provided 2012-11-26 criteria provided, single submitter clinical testing
GeneDx RCV000079959 SCV000238793 pathogenic not provided 2018-07-10 criteria provided, single submitter clinical testing Mutations in the DBT gene are associated with the autosomal recessive disorder maple syrup urine disease.The R301C missense variants in the DBT gene has been reported previously in multiple Norwegian patients with intermittent maple syrup urine disease (Brodtkorb et al., 2010). One patient who harbored R301C and a nonsense variant in the DBT gene was found to have 14% residual branched chain acyl-ketoacid dehydrogenase complex (BCKD) activity compared to wild-type, which led the authors to conclude that the R301C variant is associated with the residual enzyme activity (Brodtkorb et al., 2010).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000179836 SCV000712806 pathogenic Maple syrup urine disease 2017-03-28 criteria provided, single submitter clinical testing The p.Arg301Cys (NM001918.3 c.901C>T) variant in DBT has been reported in 7 comp ound heterozygous individuals with intermittent maple syrup urine disease (Brodt korb 2010, Axler 2014). This variant has been identified in 0.144% (96/66,682) o f European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs185492864). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessi ve carrier frequency. In vitro functional studies provide some evidence that th e p.Arg301Cys variant may impact protein function (Brodtkorb 2010). In summary, this variant meets criteria to be classified as pathogenic for maple syrup urine disease in an autosomal recessive manner based upon its biallelic occurrence in affected individuals and supported by functional studies.
Invitae RCV000179836 SCV000835510 pathogenic Maple syrup urine disease 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 301 of the DBT protein (p.Arg301Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs185492864, ExAC 0.1%). This variant has been reported in combination with another DBT variant in several individuals with intermittent maple syrup urine disease (PMID: 20570198, 21098507,27518768). ClinVar contains an entry for this variant (Variation ID: 94016). Experimental studies have shown that fibroblasts derived from individuals carrying this missense change and a second rare variant in DBT have an average of 14-36% of the BCKD enzyme activity of individuals with wild-type DBT (PMID: 20570198, 21098507). This is higher than the enzyme activity observed in cells derived from individuals with classic maple syrup urine disease, which can be 1% or less (PMID: 21098507). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000179836 SCV000893166 likely pathogenic Maple syrup urine disease 2018-10-31 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000179836 SCV001194107 likely pathogenic Maple syrup urine disease 2019-12-20 criteria provided, single submitter clinical testing NM_001918.3(DBT):c.901C>T(R301C) is classified as likely pathogenic in the context of maple syrup urine disease type II. Sources cited for classification include the following: PMID 20570198, 21098507 and 24394677. Classification of NM_001918.3(DBT):c.901C>T(R301C) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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