ClinVar Miner

Submissions for variant NM_001918.4(DBT):c.827T>G (p.Phe276Cys) (rs121964999)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079957 SCV000232150 pathogenic not provided 2013-08-23 criteria provided, single submitter clinical testing
GeneDx RCV000079957 SCV000617633 likely pathogenic not provided 2020-12-23 criteria provided, single submitter clinical testing Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20307994, 9239422, 14517957, 31980395, 1847055, 24772966, 16786533, 25087612)
Invitae RCV000179835 SCV000627814 pathogenic Maple syrup urine disease 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 276 of the DBT protein (p.Phe276Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs121964999, ExAC 0.02%). This variant has been observed in individuals with maple syrup urine disease (PMID: 1847055, 14517957, 24772966, 16786533). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.825T>G, p.Phe215Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 11943). This variant has been reported not to substantially affect DBT protein function (PMID: 1847055). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000179835 SCV000914341 pathogenic Maple syrup urine disease 2018-12-18 criteria provided, single submitter clinical testing The DBT c.827T>G (p.Phe276Cys) missense variant has been reported in five studies in which it is found in a total of seven probands with either the thiamine-responsive subtype of maple syrup urine disease MSUD (type II), or the classic form, all in a compound heterozygous state (Fisher et al. 1991; Chuang et al. 1997; Henneke et al. 2003; Rodríguez-Pombo et al. 2006; Narayanan et al. 2013). The p.Phe276Cys variant was absent from 250 controls and is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Many of the studies suggest a strong genotype-phenotype correlation with the p.Phe276Cys variant and a thiamine-responsive MSUD phenotype. Functional studies on four of the seven individuals with this variant showed enzyme activity between 3 – 40% compared to wild type activity (Chuang et al. 1997; Rodríguez-Pombo et al. 2006). Based on the collective evidence, the p.Phe276Cys variant is classified as pathogenic for maple syrup urine disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000012721 SCV000032956 pathogenic Maple syrup urine disease, thiamine-responsive, type II 1991-01-31 no assertion criteria provided literature only

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