ClinVar Miner

Submissions for variant NM_000170.3(GLDC):c.1117C>T (p.Arg373Trp)

gnomAD frequency: 0.00001  dbSNP: rs150171524
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622676 SCV000741326 pathogenic Inborn genetic diseases 2016-01-18 criteria provided, single submitter clinical testing
Mendelics RCV000666682 SCV001137745 pathogenic Glycine encephalopathy 2019-05-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000666682 SCV001381409 pathogenic Glycine encephalopathy 2024-01-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 373 of the GLDC protein (p.Arg373Trp). This variant is present in population databases (rs150171524, gnomAD 0.003%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 16601880, 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: 520959). 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%. For these reasons, this variant has been classified as Pathogenic.
DASA RCV000666682 SCV002073764 likely pathogenic Glycine encephalopathy 2022-02-05 criteria provided, single submitter clinical testing The c.1117C>T;p.(Arg373Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 520959; PMID: 16601880; 28244183) - PS4_moderate. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28244183) - PS3_supporting. The variant is present at low allele frequencies population databases (rs150171524 – gnomAD 0.00006574%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg373Trp) was detected in trans with a pathogenic variant (PMID: 16601880; 28244183) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000666682 SCV002512744 likely pathogenic Glycine encephalopathy 2022-02-21 criteria provided, single submitter clinical testing ACMG classification criteria: PS4 supporting, PM2 moderate, PM3 moderate, PP3 supporting
CeGaT Center for Human Genetics Tuebingen RCV002275092 SCV002564037 pathogenic not provided 2022-03-01 criteria provided, single submitter clinical testing
3billion RCV000666682 SCV004013779 pathogenic Glycine encephalopathy criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 28244183). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.92). The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000520959). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 16601880, 28244183). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 16601880, 28244183). A different missense change at the same codon (p.Arg373Gln) has been reported to be associated with GLDC-related disorder (ClinVar ID: VCV001452131 / PMID: 26179960). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Counsyl RCV000666682 SCV000791016 uncertain significance Glycine encephalopathy 2017-04-25 flagged submission clinical testing
Natera, Inc. RCV000666682 SCV002075787 pathogenic Glycine encephalopathy 2020-11-25 no assertion criteria provided clinical testing

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.