ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.2980G>A (p.Gly994Arg)

gnomAD frequency: 0.00001  dbSNP: rs1406713104
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664682 SCV000788683 likely pathogenic Glycine encephalopathy 2018-02-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000664682 SCV001235444 pathogenic Glycine encephalopathy 2024-02-05 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 994 of the GLDC protein (p.Gly994Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with nonketotic hyperglycinemia (PMID: 26179960, 27362913). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550058). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLDC protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLDC function (PMID: 28244183). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000664682 SCV003934334 pathogenic Glycine encephalopathy 2023-05-01 criteria provided, single submitter clinical testing Variant summary: GLDC c.2980G>A (p.Gly994Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251454 control chromosomes. c.2980G>A has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (Coughlin_2017, Swanson_2015), and observed to segregate with disease. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function showed undetectable GCS P-protein activity compared to Wildtype (Bravo-Alonso_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28244183, 27362913, 26179960). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV004629282 SCV005123566 pathogenic Inborn genetic diseases 2024-06-05 criteria provided, single submitter clinical testing The c.2980G>A (p.G994R) alteration is located in exon 25 (coding exon 25) of the GLDC gene. This alteration results from a G to A substitution at nucleotide position 2980, causing the glycine (G) at amino acid position 994 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in the homozygous state and in conjunction with other GLDC variants in individuals with features consistent with GLDC-related glycine encephalopathy; in at least one instance, the variants were identified in trans (Swanson, 2015; Coughlin, 2017; Bravo-Alonso, 2017). This amino acid position is highly conserved in available vertebrate species. In an assay testing GLDC function, this variant showed a functionally abnormal result (Bravo-Alonso, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Natera, Inc. RCV000664682 SCV002075698 pathogenic Glycine encephalopathy 2021-05-26 no assertion criteria provided clinical testing

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