ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.2186del (p.Ala729fs) (rs386833543)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049471 SCV000636375 pathogenic Non-ketotic hyperglycinemia 2016-12-02 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 18 of the GLDC mRNA (c.2186delC), causing a frameshift at codon 729. This creates a premature translational stop signal (p.Ala729Glufs*3) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLDC are known to be pathogenic. This particular variant has been reported as compound heterozygous with another pathogenic variant in one individual affected with glycine encephalopathy (PMID: 16601880). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049471 SCV001519400 pathogenic Non-ketotic hyperglycinemia 2021-03-08 criteria provided, single submitter clinical testing Variant summary: GLDC c.2186delC (p.Ala729GlufsX3) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251416 control chromosomes in gnomAD v2.1.1. However, the variant allele was found at a frequency of 0.001096 in 912 control chromosomes within the Amish subpopulation in the newer gnomAD v3.1. c.2186delC has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (e.g. Conter_2006, Swanson_2015, Coughlin_2017) and is included as a pathogenic variant in targeted testing panels for Amish communities (e.g. Crowgey_2019, Clinic for Special Children). Two ClinVar submitters (evaluation after 2014) cite 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) RCV000049471 SCV000081905 probable-pathogenic Non-ketotic hyperglycinemia no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Natera, Inc. RCV000049471 SCV001457120 pathogenic Non-ketotic hyperglycinemia 2020-09-16 no assertion criteria provided clinical testing

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