ClinVar Miner

Submissions for variant NM_000170.3(GLDC):c.1742C>G (p.Pro581Arg)

gnomAD frequency: 0.00002  dbSNP: rs772871471
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000198720 SCV000255380 likely pathogenic Non-ketotic hyperglycinemia 2013-01-29 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000198720 SCV001580111 pathogenic Non-ketotic hyperglycinemia 2023-06-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GLDC function (PMID: 28244183). 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. ClinVar contains an entry for this variant (Variation ID: 216936). This missense change has been observed in individual(s) with non-ketotic hyperglycinemia (PMID: 22206881, 28244183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs772871471, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 581 of the GLDC protein (p.Pro581Arg).
Revvity Omics, Revvity RCV000198720 SCV003826460 pathogenic Non-ketotic hyperglycinemia 2022-01-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000198720 SCV004037741 pathogenic Non-ketotic hyperglycinemia 2023-08-30 criteria provided, single submitter clinical testing Variant summary: GLDC c.1742C>G (p.Pro581Arg) 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 allele was found at a frequency of 1.6e-05 in 251466 control chromosomes. c.1742C>G has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (e.g. Bravo-Alonso_2017, Coughlin_2017, Lee_2014). 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 demonstrating undetectable glycine cleavage system P-protein activity (Bravo-Alonso_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28244183, 27362913, 25326637). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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