ClinVar Miner

Submissions for variant NM_152783.5(D2HGDH):c.685-2A>G (rs753528947)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000001929 SCV001422038 pathogenic D-2-hydroxyglutaric aciduria 1 2019-02-11 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the D2HGDH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs753528947, ExAC 0.03%). This variant has been observed to segregate with mild D-2-hydroxyglutaric aciduria in a family (PMID: 16037974). This variant is also known as IVS4-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 1855). 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 D2HGDH are known to be pathogenic (PMID: 16081310, 20020533, 21384162). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001929 SCV001448386 pathogenic D-2-hydroxyglutaric aciduria 1 2020-11-05 criteria provided, single submitter clinical testing Variant summary: D2HGDH c.685-2A>G 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: Four predict the variant abolishes a canonical 3' acceptor site and creates a new 3 acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g. Struys_2005). The variant allele was found at a frequency of 2.4e-05 in 251668 control chromosomes (gnomAD and publication data). c.685-2A>G has been reported in the literature in a homozygous state in two siblings affected with a mild form of D-2 Hydroxyglutaric Aciduria 1 (seemingly reported with incorrect nomenclature as c.687-2A>G, IVS4-2A>G). Although asymptomatic, these individuals exhibited dramtically elevated levels of D-2-hydroxyglutarate in body fluids (Struys_2005). These data indicate that the variant is likely to be associated with a mild form of disease. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000001929 SCV001526228 pathogenic D-2-hydroxyglutaric aciduria 1 2018-05-15 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported two clinically unaffected siblings with D-2- hydroxyglutaric aciduria [PMID 16037974]
OMIM RCV000001929 SCV000022087 pathogenic D-2-hydroxyglutaric aciduria 1 2005-10-01 no assertion criteria provided literature only

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