ClinVar Miner

Submissions for variant NM_000170.3(GLDC):c.911C>T (p.Pro304Leu)

gnomAD frequency: 0.00003  dbSNP: rs1207147043
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670325 SCV000795165 likely pathogenic Glycine encephalopathy 2017-10-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000670325 SCV001587924 pathogenic Glycine encephalopathy 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 304 of the GLDC protein (p.Pro304Leu). This variant is present in population databases (no rsID available, gnomAD 0.0008%). This missense change has been observed in individual(s) with glycine encephalopathy, also known as non-ketotic hyperglycinemia (PMID: 26179960, 27362913). 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: 554650). 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 RCV000670325 SCV002024841 pathogenic Glycine encephalopathy 2021-10-07 criteria provided, single submitter clinical testing
GeneDx RCV003153796 SCV003842795 likely pathogenic not provided 2022-09-16 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on GLDC function (Swanson et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26179960)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000670325 SCV004046163 likely pathogenic Glycine encephalopathy criteria provided, single submitter clinical testing This variant has been previously reported in patients with non-ketotic hyperglycinemia (PMID: 27362913, 26179960). In one patient, the c.911C>T was in compound heterozygous state with another missense variant (PMID: 26179960). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (1/282642) and thus is presumed to be rare. In silico analyses support a deleterious effect of the variant on protein function. Based on the available evidence, the c.911C>T (p.Pro304Leu) variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000670325 SCV005077258 pathogenic Glycine encephalopathy 2024-04-18 criteria provided, single submitter clinical testing Variant summary: GLDC c.911C>T (p.Pro304Leu) results in a non-conservative amino acid change located in the Glycine cleavage system P-protein, N-terminal domain (IPR049315) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD v2.1 is considered unreliable, as metrics indicate poor data quality at this position in the exome samples. However, in the genome samples, it was found at a frequency of 3.2e-05 in 31404 chromosomes. c.911C>T has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia; Swanson_2015, Coughlin_2017). 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, finding that the variant results in no detectible enzymatic activity (Swanson_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26179960, 27362913). ClinVar contains an entry for this variant (Variation ID: 554650). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005046887 SCV005679334 pathogenic Glycine encephalopathy 1 2024-04-20 criteria provided, single submitter clinical testing

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