ClinVar Miner

Submissions for variant NM_000108.5(DLD):c.875+1G>A (rs1328820332)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000012749 SCV000938780 likely pathogenic Maple syrup urine disease, type 3 2018-10-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9 of the DLD gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with dihydrolipoamide dehydrogenase deficiency (PMID: 12925875). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DLD are known to be pathogenic (PMID: 8968745, 9934985). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000012749 SCV001737694 pathogenic Maple syrup urine disease, type 3 2021-05-24 criteria provided, single submitter clinical testing Variant summary: DLD c.875+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions indicating that this variant affects splicing leading to a totally unstable mRNA (Grafakou_2003). The variant was absent in 250256 control chromosomes (gnomAD). c.875+1G>A has been reported in the literature in a compound heterozygous individual affected with Dihydrolipoamide Dehydrogenase Deficiency who developed Leigh syndrome (Grafakou_2003). Experimental evidence from muscle tissue of this individual demonstrated considerably decreased E3 and PDHc activities. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000012749 SCV000032984 pathogenic Maple syrup urine disease, type 3 2003-10-01 no assertion criteria provided literature only

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