ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs772871471
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000198720 SCV000255380 likely pathogenic Glycine encephalopathy 2013-01-29 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000198720 SCV001580111 pathogenic Glycine encephalopathy 2024-04-15 criteria provided, single submitter clinical testing 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). This variant is present in population databases (rs772871471, gnomAD 0.003%). 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. ClinVar contains an entry for this variant (Variation ID: 216936). 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.
Revvity Omics, Revvity RCV000198720 SCV003826460 pathogenic Glycine encephalopathy 2022-01-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000198720 SCV004037741 pathogenic Glycine encephalopathy 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.