ClinVar Miner

Submissions for variant NM_000170.3(GLDC):c.1382G>A (p.Arg461Gln)

gnomAD frequency: 0.00001  dbSNP: rs386833524
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049452 SCV000798906 likely pathogenic Glycine encephalopathy 2018-03-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000049452 SCV001383321 pathogenic Glycine encephalopathy 2023-11-15 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 461 of the GLDC protein (p.Arg461Gln). This variant is present in population databases (rs386833524, gnomAD 0.006%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 16601880, 26179960). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56043). 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: 26179960). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000049452 SCV002024840 pathogenic Glycine encephalopathy 2019-07-30 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003407429 SCV004109147 pathogenic GLDC-related disorder 2023-02-01 criteria provided, single submitter clinical testing The GLDC c.1382G>A variant is predicted to result in the amino acid substitution p.Arg461Gln. This variant has been reported in the compound heterozygous state in multiple individuals with non-ketotic hyperglycinemia (Conter et al 2006. PubMed ID: 16601880; Suzuki Y et al 2010. PubMed ID: 20691948; Coughlin CR et al 2016. PubMed ID: 27362913; Farris et al. 2020. PubMed ID: 32421718). Functional studies have shown that this variant has the measurable residual activity of 0.5 to 1% of control (Swanson MA et al 2015. PubMed ID: 26179960). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-6592870-C-T). This variant is interpreted as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049452 SCV000081886 probable-pathogenic Glycine encephalopathy no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Natera, Inc. RCV000049452 SCV002075776 pathogenic Glycine encephalopathy 2021-06-11 no assertion criteria provided clinical testing

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