ClinVar Miner

Submissions for variant NM_000108.5(DLD):c.104dup (p.Tyr35Ter) (rs753234219)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Myriad Women's Health, Inc. RCV000409901 SCV001194023 pathogenic Maple syrup urine disease, type 3 2019-12-17 criteria provided, single submitter clinical testing NM_000108.3(DLD):c.104dupA(Y35*) is classified as pathogenic in the context of dihydrolipoamide dehydrogenase deficiency. Sources cited for classification include the following: PMID 9298831 and 8968745. Classification of NM_000108.3(DLD):c.104dupA(Y35*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV000409901 SCV001219534 pathogenic Maple syrup urine disease, type 3 2020-07-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr35*) in the DLD gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs753234219, ExAC 0.02%). This variant has been observed in multiple individuals affected with dihydrolipoamide dehydrogenase deficiency (PMID: 8968745, 9934985). ClinVar contains an entry for this variant (Variation ID: 370072). Loss-of-function variants in DLD are known to be pathogenic (PMID: 8968745, 9934985). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000409901 SCV001337760 pathogenic Maple syrup urine disease, type 3 2020-01-10 criteria provided, single submitter clinical testing Variant summary: DLD c.104dupA (p.Tyr35X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 250616 control chromosomes (gnomAD). c.104dupA has been reported in the literature in individuals (in compound heterozygous state) affected with Dihydrolipoamide Dehydrogenase Deficiency (MSUD Type 3) (Hong_1996, Shaag_1999). These data indicate that the variant may be associated with disease. Biochemical studies report this variant effect results in decreasing normal activity (Hong_1996, Shaag_1999). One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001591045 SCV001817321 pathogenic not provided 2020-09-29 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 9298831, 18362926, 23995961, 7815230, 15712224, 9934985, 20672374, 25356417, 8968745)
OMIM RCV000409901 SCV000032980 pathogenic Maple syrup urine disease, type 3 2005-03-01 no assertion criteria provided literature only
Natera, Inc. RCV000409901 SCV001464049 pathogenic Maple syrup urine disease, type 3 2020-09-16 no assertion criteria provided clinical testing

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