ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.1580+2T>G (rs1554646710)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000560119 SCV000636359 pathogenic Non-ketotic hyperglycinemia 2019-08-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the GLDC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in GLDC are known to be pathogenic. This particular variant has been reported in the literature as a compound heterozygote in individuals affected with nonketotic hyperglycemia (glycine encephalopathy) (PMID: 26179960). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000560119 SCV000799055 pathogenic Non-ketotic hyperglycinemia 2018-04-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000560119 SCV000919470 pathogenic Non-ketotic hyperglycinemia 2018-05-25 criteria provided, single submitter clinical testing Variant summary: GLDC c.1580+2T>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: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 121382 control chromosomes. c.1580+2T>G has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity measured as an elevation of CSF and plasma glycine levels. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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