Submissions for variant NM_000170.3(GLDC):c.245T>C (p.Leu82Ser)

dbSNP: rs386833559

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671778	SCV000796797	uncertain significance	Non-ketotic hyperglycinemia	2017-12-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671778	SCV001414075	pathogenic	Non-ketotic hyperglycinemia	2023-09-26	criteria provided, single submitter	clinical testing	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 not expected to disrupt GLDC protein function. This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 82 of the GLDC protein (p.Leu82Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GLDC-related conditions (PMID: 26179960). 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: 555868). This variant disrupts the p.Leu82 amino acid residue in GLDC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15192636, 26179960). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002225714	SCV002504261	pathogenic	not provided	2021-01-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced enzyme activity (Swanson et al., 2015); 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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526747	SCV005039210	uncertain significance	not specified	2024-03-22	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.245T>C (p.Leu82Ser) 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 is considered unreliable, as metrics indicate poor data quality at this position. c.245T>C has been reported in the literature in an individual affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia; Swanson_2015). These data do not allow any conclusion about variant significance. This publication also reports experimental evidence evaluating an impact on protein function, finding that the variant results in 30%-50% of normal activity. The following publication has been ascertained in the context of this evaluation (PMID: 26179960). ClinVar contains an entry for this variant (Variation ID: 555868). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.