ClinVar Miner

Submissions for variant NM_000170.3(GLDC):c.2368C>T (p.Arg790Trp)

gnomAD frequency: 0.00001  dbSNP: rs386833556
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000049484 SCV000963027 pathogenic Non-ketotic hyperglycinemia 2023-04-20 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: 15192636, 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 not expected to disrupt GLDC protein function. ClinVar contains an entry for this variant (Variation ID: 56075). This missense change has been observed in individual(s) with glycine encephalopathy (nonketotic hyperglycinemia) (PMID: 15192636, 16450403, 27362913, 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 (rs386833556, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 790 of the GLDC protein (p.Arg790Trp).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV004593981 SCV002558013 pathogenic Glycine encephalopathy 1 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glycine encephalopathy (MIM#605899). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 3 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 8 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. p.(Arg790Gln) has been reported in a control individual and zygosity is unclear (PMID: 29232014). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple homozygote and compound heterozygote individuals with nonketotic hyperglycinemia also known as glycine encephalopathy (ClinVar, PMIDs: 28244183, 27362913, 15192636). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Studies have shown mutant results in reduced enzyme activity of around 15% compared to the wild-type (PMIDs: 28244183, 15192636). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049484 SCV004223845 pathogenic Non-ketotic hyperglycinemia 2023-11-01 criteria provided, single submitter clinical testing Variant summary: GLDC c.2368C>T (p.Arg790Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2368C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (e.g., Kure_2004, Bravo-Alonso_2017, Coughlin_2019). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant resulted in approximately 15% of normal activity (e.g., Kure_2004, Bravo-Alonso_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28244183, 27362913, 15192636). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Two submitters classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049484 SCV000081918 probable-pathogenic Non-ketotic hyperglycinemia no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000049484 SCV000845322 uncertain significance Non-ketotic hyperglycinemia 2018-08-07 flagged submission clinical testing

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