ClinVar Miner

Submissions for variant NM_000170.3(GLDC):c.1033C>A (p.Pro345Thr)

gnomAD frequency: 0.00001  dbSNP: rs373263202
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670628 SCV000795503 uncertain significance Glycine encephalopathy 2017-11-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000670628 SCV001584391 pathogenic Glycine encephalopathy 2025-01-23 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 345 of the GLDC protein (p.Pro345Thr). This variant is present in population databases (rs373263202, gnomAD 0.002%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 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: 554913). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GLDC protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004586864 SCV005077097 uncertain significance not specified 2024-04-22 criteria provided, single submitter clinical testing Variant summary: GLDC c.1033C>A (p.Pro345Thr) 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 variant allele was found at a frequency of 8e-06 in 251356 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1033C>A has been reported in the literature in an individual affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia; Coughlin_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27362913). ClinVar contains an entry for this variant (Variation ID: 554913). Based on the evidence outlined above, the variant was classified as uncertain significance.

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