ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.2316-1G>A (rs386833554)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049482 SCV000636382 pathogenic Non-ketotic hyperglycinemia 2019-10-15 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 19 of the GLDC 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 (rs386833554, ExAC 0.005%). This variant has been observed in in several individuals affected with glycine encephalopathy/nonketotic hyperglycinemia (PMID: 16601880, 27362913). ClinVar contains an entry for this variant (Variation ID: 56073). 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 GLDC are known to be pathogenic (PMID: 16601880). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000734579 SCV000862731 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000049482 SCV001363789 pathogenic Non-ketotic hyperglycinemia 2019-11-07 criteria provided, single submitter clinical testing Variant summary: GLDC c.2316-1G>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: Two predict that the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 248604 control chromosomes (gnomAD). c.2316-1G>A has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia; e.g. Conter_2006, Swanson_2015, Coughlin_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049482 SCV000081916 probable-pathogenic Non-ketotic hyperglycinemia no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Counsyl RCV000049482 SCV000792415 pathogenic Non-ketotic hyperglycinemia 2017-06-23 no assertion criteria provided clinical testing

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