Submissions for variant NM_000170.3(GLDC):c.707G>C (p.Arg236Pro)

dbSNP: rs772832052

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002015130	SCV002283122	likely pathogenic	Glycine encephalopathy	2023-06-16	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 1494920). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 27362913). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 236 of the GLDC protein (p.Arg236Pro).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699626	SCV005204463	uncertain significance	not specified	2024-06-26	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.707G>C (p.Arg236Pro) 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 4e-06 in 251476 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.707G>C has been reported in the literature in a compound heterozygous individual affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) but the phase of the two variants were undetermined (Coughlin_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27362913). ClinVar contains an entry for this variant (Variation ID: 1494920). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV004719219	SCV005325902	likely pathogenic	not provided	2023-06-09	criteria provided, single submitter	clinical testing	Reported with a second GLDC variant, phase unknown, in a patient with suspected nonketotic hyperglycinemia in published literature (Coughlin et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27362913)